Compounds having muscarinic receptor antagonist and beta2 adrenergic receptor agonist activity

ABSTRACT

Compounds of formula I, defined herein, act both as muscarinic receptor antagonists and beta2 adrenergic receptor agonists and are useful for treating broncho-obstructive and inflammatory diseases.

CROSS REFERENCES TO RELATED APPLICATIONS

This application claims priority to European Patent Application No15154917.7, filed on Feb. 12, 2015, which is incorporated herein byreference in its entirety.

BACKGROUND OF THE INVENTION

Field of the Invention

The present invention relates to compounds which act both as muscarinicreceptor antagonists and beta2 adrenergic receptor agonists. The presentinvention also relates to processes for the preparation of such acompound, compositions which contain such a compound, certaintherapeutic uses of such a compound, and combinations of such a compoundwith other pharmaceutical active ingredients.

Discussion of the Background

Pulmonary disorders, such as asthma and chronic obstructive pulmonarydisease (COPD), are commonly treated with bronchodilators. A well-knownclass of bronchodilators consists of beta-2 adrenergic receptoragonists, such as salbutamol, fenoterol, formoterol and salmeterol.These compounds are generally administered by inhalation.

Another well-known class of bronchodilators consists of muscarinicreceptor antagonists (anticholinergic compounds), such as ipratropiumand tiotropium. These compounds are also typically administered byinhalation.

Inhaled formulations of both beta-2 agonists and muscarinic receptorantagonists are valuable agents in the treatment of asthma and COPD,with both classes of agents providing symptomatic relief due to theirability to relax constricted airways. Observations that thebronchodilator effects of the two classes of agents were additive,prompted studies with combinations of the two agents. In 1975, it wasshown that beneficial effects could be achieved by combining twoingredients such as fenoterol and ipratropium bromide in a singleaerosol. This prompted the development of fixed dose combinations ofipratropium bromide firstly with fenoterol (Berodual, introduced in1980), and then with salbutamol (Combivent, introduced in 1994).

More recently the availability of both long-acting muscarinicantagonists and long-acting beta-2 agonists prompted the development ofcombinations of these agents. For example, WO 00/69468, which isincorporated herein by reference in its entirety, discloses medicamentcompositions containing a muscarinic receptor antagonist, such astiotropium bromide, and beta-2 adrenergic receptor agonists, such asformoterol fumarate or salmeterol, and WO 2005/115467, which isincorporated herein by reference in its entirety, discloses acombination which comprises a beta-2 agonist and an antagonist of M3muscarinic receptors which is a salt of3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane.

An alternative approach to the development of fixed dose combinations isthe identification of molecules that combine both activities ofmuscarinic antagonism and beta-2 agonism. In fact compounds possessingboth beta-2 adrenergic receptor agonist and muscarinic receptorantagonist activity are highly desirable since such bifunctionalcompounds would provide bronchodilation through two independentmechanisms of action while having a single molecule pharmacokinetics.

Such kind of compounds was described in some patent applications, suchas WO 2004/074246, WO 2004/074812, WO 2005/051946, WO 2006/023457, WO2006/023460, WO 2010/123766, WO 2011/048409 and co-pending patentapplications WO 2012/168349, WO 2012/168359, WO2014/086924, and WO2014/086927, all of which are incorporated herein by reference in theirentireties.

It has now been found that some particular aryl or heteroarylhydroxyacetic ester derivatives, besides possessing both beta-2adrenergic receptor agonist and muscarinic receptor antagonist activity,possess elevated affinity for the M3 muscarinic receptors and longlasting bronchodilating activity.

SUMMARY OF THE INVENTION

Accordingly, it is one object of the present invention to provide novelcompound which act both as muscarinic receptor antagonists and beta2adrenergic receptor agonists.

It is another object of the present invention to provide novel processesfor the preparation of such a compound.

It is another object of the present invention to provide novelcompositions which contain such a compound.

It is another object of the present invention to provide noveltherapeutic uses of such a compound.

It is another object of the present invention to provide novelcombinations of such a compound with other pharmaceutical activeingredients, for example, those currently used in the treatment ofrespiratory disorders, e.g. corticosteroids, P38 MAP kinase inhibitors,IKK2, HNE inhibitors, PDE4 inhibitors, leukotriene modulators, NSAIDsand mucus regulators.

These and other objects, which will become apparent during the followingdetailed description, have been achieved by the inventors' discovery ofthe compounds of formula I, defined below.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

In particular, the invention is directed to compounds of general formula

whereinQ is a group of formula

Y is selected from Y2 and Y1 which are divalent groups of formula

wherein

A1 and A2 are independently absent or selected from (C₁-C₁₂)alkylene,(C₃-C₈)cycloalkylene and (C₃-C₈)heterocycloalkylene optionallysubstituted by one or more substituents selected from (C₁-C₆)alkyl,aryl(C₁-C₆)alkyl, and heteroaryl(C₁-C₆)alkyl;

B is absent or is selected from (C₃-C₈)cycloalkylene,(C₃-C₈)heterocycloalkylene, arylene or heteroarylene optionallysubstituted by one or more groups selected from —OH, halogens, —CN,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆)haloalkoxy, andaryl(C₁-C₆)alkyl;

C is absent or is selected from —O—, —C(O)—, —OC(O)—, —(O)CO—, —S—,—S(O)—, —S(O)₂— and —N(R₇)—, or is one of the following groups C1-C23

wherein R₇ is in each occurrence independently H or selected from linearor branched (C₁-C₈)alkyl, aryl(C₁-C₆)alkyl, arylsulfanyl, arylsulfinyl,arylsulfonyl, (C₃-C₈)cycloalkyl, (C₃-C₈)heterocycloalkyl, aryl, andheteroaryl;

D is absent or is selected from (C₁-C₁₂)alkylene, (C₂-C₁₂)alkenylene,(C₂-C₆)alkynylene, arylene, heteroarylene, (C₃-C₈)cycloalkylene,(C₃-C₈)heterocycloalkylene; said arylene, heteroarylene,(C₃-C₈)cycloalkylene and (C₃-C₈)heterocycloalkylene being optionallysubstituted by one or more groups selected from —OH, halogen, —CN,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)haloalkyl, (C₁-C₆)haloalkoxy andaryl(C₁-C₆)alkyl;

n is at each occurrence independently 0 or an integer from 1 to 3;

m is at each occurrence independently an integer from 1 to 3;

E is absent or is selected from —O—, —NR₇—, —NR₇—C(O)—, —C(O)—NR₇—,—OC(O)—, —C(O)—(CH₂)_(n)—O—; —NR₇—C(O)—(CH₂)_(n)—O—, —NR₇—C(O)—NR₇— and—S—;

G is arylene or heteroarylene, optionally substituted by one or moresubstituents selected from halogen atoms, —OH, oxo (═O), —SH, —NO₂, —CN,—CON(R₆)₂, —NH₂, —NHCOR₆, —CO₂R₆, (C₁-C₁₀)alkylsulfanyl,(C₁-C₁₀)alkylsulfinyl, (C₁-C₁₀)alkylsulfonyl, (C₁-C₁₀)alkyl, aryl,haloaryl, heteroaryl, and (C₁-C₁₀)alkoxy;

R₁ is selected from (C₃-C₈)cycloalkyl, (C₃-C₈)heterocycloalkyl, aryl,heteroaryl, aryl(C₁-C₆)alkyl, heteroaryl(C₁-C₆)alkyl and(C₃-C₈)cycloalkyl(C₁-C₆)alkyl, optionally substituted by one or moregroup selected independently from halogen, (C₁-C₈)alkyl, and(C₁-C₁₀)alkoxy;

s is 0 or an integer from 1 to 3;

R₂ is a nitrogen containing group which may be selected from:

-   -   a group (a) which is —NR₃R₄ wherein R₃ and R₄ are independently        hydrogen or (C₁-C₄) alkyl; and    -   a group (b) of formula J1, J2, J3, J4 or J5

R₅ is a group of formula K

wherein p is 0 or an integer from 1 to 4; q is 0 or an integer from 1 to4;

P is absent or is selected from the divalent group consisting of O, S,SO, SO₂, CO, NR₆ CH═CH, N(R₆)SO₂, N(R₆)COO, N(R₆)C(O), SO₂N(R₆),OC(O)N(R₆), and C(O)N(R₆);

W is selected from H, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, aryl, andheteroaryl, optionally substituted by one or more substituents selectedindependently from halogen atoms, —OH, oxo (═O), —SH, —NO₂, —CN,—CON(R₆)₂, —NH₂, —NHCOR₆, —CO₂R₆, (C₁-C₁₀)alkylsulfanyl,(C₁-C₁₀)alkylsulfinyl, (C₁-C₁₀)alkylsulfonyl, (C₁-C₁₀)alkyl, and(C₁-C₁₀)alkoxy;

R₆ is at each occurrence independently H or selected from (C₁-C₁₀)alkyl,(C₁-C₆)haloalkyl, (C₂-C₆)alkynyl, (C₂-C₆)alkenyl, (C₃-C₈)cycloalkyl,heteroaryl and aryl optionally substituted by one or more substituentsselected from halogen atoms, —OH, oxo (═O), —SH, —NO₂, —CN, —CONH₂,—COOH, (C₁-C₁₀)alkoxycarbonyl, (C₁-C₁₀)alkylsulfanyl,(C₁-C₁₀)alkylsulfinyl, (C₁-C₁₀)alkylsulfonyl, (C₁-C₁₀)alkyl and(C₁-C₁₀)alkoxy;

and pharmaceutically acceptable salts or solvates thereof.

The term “pharmaceutically acceptable salts”, as used herein, refers tocompounds according to the invention obtained by converting any of thefree acid or basic group, if present, into the corresponding additionsalt with any base or acid conventionally intended as beingpharmaceutically acceptable.

Suitable examples of said salts may thus include mineral or organic acidaddition salts of basic residues such as amino groups, as well asmineral or organic basic addition salts of acid residues such ascarboxylic groups.

Cations of inorganic bases which can be suitably used to prepare saltswithin the invention comprise ions of alkali or alkaline earth metalssuch as potassium, sodium, calcium or magnesium.

Those obtained by reacting the main compound, functioning as a base,with an inorganic or organic acid to form a salt comprise, for example,salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoricacid, methane sulfonic acid, camphor sulfonic acid, acetic acid, oxalicacid, maleic acid, fumaric acid, succinic acid and citric acid.

Those skilled in the art of organic chemistry will appreciate that manyorganic compounds can form complexes with solvents in which they arereacted or from which they are precipitated or crystallized. Thesecomplexes are known as “solvates”. Pharmaceutically acceptable solvatesof compound of the invention are within the scope of the invention.

Included within the scope of the present invention are also polymorphsand crystalline forms of compounds of formula (I), or ofpharmaceutically acceptable salts, or solvates thereof.

The terms “halogen,” “halogens,” and “halogen atoms” as used hereininclude fluorine, chlorine, bromine, and iodine, preferably chlorine orfluorine, referring independently to one or more of these atoms.

The expression “(C₁-C_(x))alkyl” refers to straight or branched chainalkyl groups wherein the number of carbon atoms is from 1 to x,preferably from 1 to 6 thus referring to (C₁-C₆)alkyl. Examples ofgroups are methyl, ethyl, n-propyl, isopropyl, t-butyl, pentyl, hexyl,octyl, nonyl, decyl, undecyl, dodecyl, and the like.

In an analogous manner, the expression “(C₁-C_(x))alkylene” herewithrefers to divalent groups wherein the number of carbon atoms is from 1to x, preferably from 1 to 6 thus referring to (C₁-C₆)alkylene, such asmethylene, ethylene, n-propylene, isopropylene, n-butylene, t-butylene,pentylene, hexylene, octylene, nonylene, decylene, undecylene,dodecylene and the like. With alternative common name, deriving from thename of the corresponding alkanes, the above divalent groups can bereferred to also as methanediyl, ethanediyl, n-propanediyl,propan1,2diyl, and the like.

The expression “(C₁-C₆)haloalkyl” refers to the above “(C₁-C₆)alkyl”group wherein one or more hydrogen atoms are replaced by one or morehalogen atoms, which can be the same or different from each other.

Examples of said (C₁-C₆)haloalkyl groups include halogenated,poly-halogenated and fully halogenated alkyl groups wherein one or moreof the hydrogen atoms are replaced by halogen atoms, e.g.trifluoromethyl group.

The expression “hydroxy(C₁-C₆)alkyl” likewise refers to -alkyl-OHgroups.

The expressions “(C₁-C₁₀)alkylsulfanyl,” “(C₁-C₁₀)alkylsulfinyl,” or“(C₁-C₁₀)alkylsulfonyl” refer, respectively, to alkyl-S—, alkyl-SO— oralkyl-SO₂— groups.

The expression “(C₂-C_(x))alkenyl” refers to straight or branched carbonchains with one or more double bonds, wherein the number of carbon atomsis from 1 to x. Examples of said groups comprise ethenyl, propenyl,butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl,undecenyl, dodecenyl and the like.

In an analogous manner, the expression “(C₂-C_(x))alkenylene” refers todivalent groups, such as ethenylene, propenylene, butenylene,pentenylene, hexenylene, heptenylene, octenylene, nonenylene,decenylene, undecenylene, dodecenylene, and the like.

The expression “(C₂-C_(x))alkynyl” refers to straight or branched carbonchains with one or more triple bonds, wherein the number of carbon atomsis from 1 to x. Examples of said groups comprise ethynyl, propynyl,butynyl, pentynyl, hexynyl, and the like.

In an analogous manner, the expression “(C₂-C₆)alkynylene” refers todivalent groups, such as ethynylene, propynylene, butynylene,pentynylene, hexynylene, and the like; otherwise commonly referred to asethynediyl, propynediyl, butyndiyl and the like.

The expression “(C₁-C_(x))alkoxy” refers to alkyl-oxy (i.e. alkoxy)groups, being the alkyl portion as above defined, wherein the number ofcarbon atoms is from 1 to x. Examples of said groups comprise methoxy(i.e. CH₃O—), ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy,sec-butoxy, tert-butoxy, pentoxy, hexoxy, and the like.

The expression “(C₁-C₆)haloalkoxy” refers to the above “(C₁-C₆)alkoxy”group wherein one or more hydrogen atoms are replaced by one or morehalogen atoms, which can be the same or different from each other.

Examples of said (C₁-C₆)haloalkoxy groups include halogenated,poly-halogenated and fully halogenated alkoxy groups wherein one or moreof the hydrogen atoms are replaced by halogen atoms, e.g.trifluoromethoxy group.

The expression “(C₁-C₁₀)alkoxycarbonyl” refers to (C₁-C₁₀)alkoxyC(O)—groups. Non limiting examples of (C₁-C₁₀)alkoxycarbonyl may thus includemethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl,isopropoxycarbonyl, and the like.

The expression “(C₃-C₈)cycloalkyl” refers to mono or bi-cycloaliphatichydrocarbon groups with 3 to 8 carbon atoms. Examples includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,bicyclo[2.2.1]hept-2-yl and the like.

The expression “(C₃-C₈)heterocycloalkyl” refers to saturated orpartially saturated monocyclic (C₃-C₈)cycloalkyl groups, in which atleast one ring carbon atom is replaced by a heteroatom or heteroaromaticgroup (e.g. N, NH, S or O). Examples include quinuclidinyl,pyrrolidinyl, piperidinyl, azabicyclo[3.2.1]octan-3-yl andazoniabicyclo[2.2.2]octanyl, [1.2.3.6]tetrahydropyridin-1yl and thelike.

In an analogous manner, the expressions “(C₃-C₈)cycloalkylene” and“(C₃-C₈)heterocycloalkylene” herewith refer to divalent groups. The termcycloalkylene refers to saturated cycloalkane-diyl and partiallysaturated monocyclic groups such as cycloalkene-diyl. Examples of such(C₃-C₈)cycloalkylene and (C₃-C₈)heterocycloalkylene are divalent groups,such as, respectively, cyclopropylene, cyclobutylene, cyclopentylene,cyclohexylene, cycloheptylene, bicyclo[2.2.1]hept-2-ylene andquinuclidinylene, pyrrolidinylene, piperidinylene,azabicyclo[3.2.1]octan-3-ylene, azoniabicyclo[2.2.2]octanylene,[1.2.3.6]tetrahydropyridin-[1.4]diyl, and the like. With alternativecommon name, deriving from the name of the corresponding alkanes oralkenes, the above divalent groups can be referred to also ascyclopropanediyl, cyclobutanediyl, cyclopentanediyl, cyclohexanediyl,cycloheptanediyl, bicyclo[2.2.1]heptaendiyl and quinuclidinediyl,pyrrolidinediyl, piperidinediyl, azabicyclo[3.2.1]octandiyl,azoniabicyclo[2.2.2]octandiyl, [1.2.3.6]tetrahydropyridine-[1.4]diyl,and the like.

The expression “aryl” refers to mono, bi- or tricyclic ring systemshaving 5 to 20, preferably from 5 to 15, more preferably from 5 to 8ring atoms, and wherein at least one ring is aromatic.

The expression “heteroaryl” refers to mono, bi- or tri-cyclic systemswith 5 to 20 ring atoms, preferably from 5 to 15, in which at least onering is aromatic and in which at least one carbon ring atom is aheteroatom or heteroaromatic group (e.g. N, NH, S or O).

Examples of suitable aryl or heteroaryl monocyclic systems include, forinstance, thiophene (thiophenyl), benzene (phenyl), pyrrole (pyrrolyl),pyrazole (pyrazolyl), imidazole (imidazolyl), isoxazole (isoazolyl),oxazole (oxazolyl), isothiazole (isothiazolyl), thiazole (thiazolyl),pyridine (pyridinyl), imidazolidine (imidazolidinyl), furan (furanyl)radicals, and the like.

Examples of suitable aryl or heteroaryl bicyclic systems includenaphthalene (naphthalenyl), biphenylene (biphenylenyl), purine(purinyl), pteridine (pteridinyl), benzotriazole (benzotriazolyl),quinoline (quinolinyl), isoquinoline (isoquinolinyl), indole (indolyl),isoindole (isoindolyl), benzothiophene (benzothiophenyl), dihydrobenzodioxin, dihydro-indene, dihydrobenzo dioxepin, benzo oxazine radicals,and the like.

Examples of suitable aryl or heteroaryl tricyclic systems includefluorene radicals as well as benzocondensed derivatives of theaforementioned heteroaryl bicyclic systems.

In an analogous manner, the expressions “arylene” and “heteroarylene”refer to divalent groups, such a phenylene, biphenylene and thienylene.Such groups are also commonly named as “arenediyl” or “heteroarenediyl”groups. e.g. ortho-phenylene is also named benzene-1,2-diyl,para-phenylene is also named benzene-1,4-diyl, meta-phenylene is alsonamed benzene-1,3-diyl.

The expressions “aryl(C₁-C₆)alkyl”, “heteroaryl(C₁-C₆)alkyl” and“(C₃-C₈)cycloalkyl(C₁-C₆)alkyl” refer to a “(C₁-C₆)alkyl” respectivelysubstituted by one or more aryl, heteroaryl or (C₃-C₈)cycloalkyl groups,as defined above.

Examples of aryl(C₁-C₆)alkyl include triphenylmethyl.

By way of analogy the expressions “arylsulfanyl,” “arylsulfinyl,” and“arylsulfonyl” refer, respectively, to aryl-S—, aryl-SO— or aryl-SO₂—groups. Preferred groups are phenyl-S—, phenyl-SO— or phenyl-SO₂—.

Likewise the expression “haloaryl” refers to the above “aryl” groupwherein one or more hydrogen atoms are replaced by one or more halogenatoms, which can be the same or different from each other.

As used herein an oxo moiety is represented by (O) as an alternative toother common representations, e.g. (═O). Thus, in terms of generalformula, the carbonyl group is herein preferably represented as —C(O)—as an alternative to the other common representations such as —CO—,—(CO)— or —C(═O)—. In general, the parenthetical group is a lateralgroup, not included into the chain, and parentheses are used, whendeemed useful, to help disambiguating linear chemical formulas; e.g. thesulfonyl group —SO₂— might be also represented as —S(O)₂— todifferentiate e.g. with respect to the sulfinic group —S(O)O—.

Whenever basic amino or quaternary ammonium groups are present in thecompounds of formula I, as above said, physiological acceptable anions,selected among chloride, bromide, iodide, trifluoroacetate, formate,sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate,citrate, fumarate, tartrate, oxalate, succinate, benzoate,p-toluenesulfonate, pamoate and naphthalene disulfonate may be present.Likewise, in the presence of acidic groups such as —COOH groups,corresponding physiological cation salts may be present as well, forinstance including alkaline or alkaline earth metal ions.

It will be apparent to those skilled in the art that compounds ofgeneral formula I contain at least two stereogenic centers. Therefore,the present invention also includes any of the optical stereoisomers,diastereoisomers, and mixtures thereof, in any proportion.

In particular, the carbon atom (2) linked to R₁, —OH, G and C═O groups,and the carbon atom (1) linked to Q, —OH and the rest of the molecule,represent stereogenic centers.

Thus, compounds according to the present invention, having at least twostereogenic centers, they may accordingly exist as at least fourdiastereoisomers. Where the compounds according to the invention possessmore than two stereogenic centers, they will exist as 2″diastereoisomers (wherein n here refers to the number of stereogeniccenters). It is to be understood that all such isomers and mixturesthereof in any proportion are encompassed within the scope of thepresent invention.

In a preferred embodiment, the invention is directed to compounds offormula (I)′, which are compounds of formula (I) as above defined wherethe absolute configuration of carbon (1) is that shown herebelow:

The absolute configuration for a chiral carbon is determined via X rayand assigned on the basis of Cahn-Ingold-Prelog nomenclature based ongroups' priorities.

Thus, in one preferred embodiment, for compounds of formula (I),absolute configuration at carbon (1) is (R).

As above said, compounds of formula (I) may exist as at least fourdiastereoisomers (Ia), (Ib), (Ic), and (Id) herebelow represented, whichare comprised within the scope of the present invention; eachdiastereoisomer (Ia), (Ib), (Ic), and (Id) may be constituted by amixture of corresponding epimers when a third stereogenic center ispresent in the molecule.

In a further preferred embodiment, the present invention is directed tocompounds of formula (Ia) or (Ib), which are respectively compounds offormula (I) as above defined wherein the absolute configuration atcarbon (1) is (R) and at carbon (2) is (R); or wherein the absoluteconfiguration at carbon (1) is (R) and at carbon (2) is (S).

It is to be understood that all preferred groups or embodimentsdescribed herebelow and hereabove for compounds of formula (I) may becombined among each other and apply to compounds of formula (Ia), (Ib),(Ic), (Id), and (I)′ as well mutatis mutandis.

In a first preferred embodiment the invention is directed to group ofcompounds of general formula I wherein R₂ is a group of formula J3:

R₅ is a group of formula K, wherein p is 0 or 1, P is absent or is CO, qis absent or is 1 and W is H or is selected from (C₁-C₆)alkyl and aryl,and all the other variables are as defined above.

In a more preferred embodiment, R₂ is a group of formula J3, R₅ ismethyl or benzyl, and all the other variables are as defined above.

In another preferred embodiment, G is arylene and R₁ is aryl, optionallysubstituted by one or more group independently selected from halogen,(C₁-C₈)alkyl and (C₁-C₁₀)alkoxy.

In a further preferred embodiment A1 and A2 are independently absent orselected from methylene, ethylene, propylene, butylene, pentylene,hexylene, heptylene, octylene and nonylene, G is phenylene, and R₁ isphenyl, optionally substituted by one or more group selectedindependently from halogen, (C₁-C₈)alkyl and (C₁-C₁₀)alkoxy, and all theother variables are as defined above.

In this first preferred embodiment when R₁ is a phenyl group substitutedby one or more groups independently selected from halogen, (C₁-C₈)alkyland (C₁-C₁₀)alkoxy; it is preferred that R₁. is substituted in paraand/or meta position.

In another preferred embodiment E is —O— or —C(O)—(CH₂)_(n)—O— or—NR₇—C(O)—(CH₂)_(n)—O—; G is phenylene wherein E is linked to the phenylring G in meta position, and R1 is phenyl, optionally substituted by oneor more group selected from halogen, (C₁-C₈)alkyl or (C₁-C₁₀)alkoxygroups.

Also in this other preferred embodiment, when R₁ is phenyl substitutedby one or more group selected from halogen, (C₁-C₈)alkyl or(C₁-C₁₀)alkoxy groups, it is preferred that R₁ is substituted in paraand/or meta position.

Most preferred compounds in this other preferred embodiment are thosecompounds of formula (I) wherein Y is Y2;

A2 is absent and A1 is independently selected from (C₁-C₁₂)alkylenewhich is methylene, ethylene, n-propylene, butylene, pentylene,hexylene, heptylene, octylene;

B is absent or is selected from (C₃-C₈)heterocycloalkylene which ispiperidinylene, arylene which is phenylene and heteroarylene which ispyridine-diyl; B being optionally substituted by one or more groupsselected independently from —OH, halogen which is fluorine, chlorine,bromine, (C₁-C₆)alkoxy which is methoxy, ethoxy, isopropoxy,(C₁-C₆)haloalkyl which is trifluoromethyl and (C₁-C₆)haloalkoxy which istrifluoromethoxy;

C is absent or is selected from —C(O)—, or is one of the followinggroups C1, C2, C7, C8, C9, C10, C12, C13, C14, C15, C16, C17, C18, C19,C20, C21, C23; wherein R₇ is H;

D is absent or is selected from arylene which is para-phenylene ormeta-phenylene, (C₃-C₈)cycloalkylene which is cyclohexanediyl,(C₃-C₈)heterocycloalkylene which is piperidindiyl, pyrrolidindiyl,azetidindiyl;

n is at each occurrence independently 0 or an integer from 1, 2 or 3;

m is at each occurrence independently an integer from 1, 2 or 3;

E is absent or is selected from —O—, —C(O)—(CH₂)_(n)—O— which is—C(O)—CH₂—O—; —NR₇—C(O)—(CH₂)_(n)—O— which is —NH—C(O)—CH₂—O—;

G is arylene which is meta-phenylene;

R₁ is selected from thiophenyl, cyclohexyl or phenyl optionallysubstituted in para and/or meta position by one or more groups selectedindependently from fluorine, methyl, ethyl;

s is 1;

R₂ is J3 wherein R₅ is benzyl

and pharmaceutically acceptable salts or solvates thereof.

A second preferred group of compounds is that of general formula Iwherein R₂ is a nitrogen containing group selected from J1, J2, or J5

and all the other variables as defined above.

Particularly preferred compounds of formula I are those wherein

Y is a divalent groups of formula

A2 is absent and A1 is independently selected from (C₁-C₁₂)alkylenewhich is methylene, ethylene, n-propylene, isopropylene, butylene,pentylene, hexylene, heptylene, or octylene;

B is absent or is selected from (C₃-C₈)heterocycloalkylene which ispiperidinylene, arylene which is phenylene, or heteroarylene which ispyridine-diyl, pyrazole-diyl; B being optionally substituted by one ormore groups selected from —OH, halogen which is fluorine, chlorine,bromine, —CN, (C₁-C₆)alkyl which is methyl, (C₁-C₆)alkoxy which ismethoxy, ethoxy, isopropoxy, (C₁-C₆)haloalkyl which is trifluoromethyland (C₃-C₆)haloalkoxy which is trifluoromethoxy;

C is absent or is selected from —O—, —C(O)—, or is one of the followinggroups C1, C2, C4, C7, C8, C9, C10, C12, C13, C14, C15, C16, C17, C18,C19, C20, C21 C22 C23, wherein R₇ is in each occurrence independently Hor selected from (C₁-C₈)alkyl which is methyl, ethyl andaryl(C₁-C₆)alkyl which is benzyl;

D is absent or is selected from arylene which is para-phenylene ormeta-phenylene, (C₃-C₈)cycloalkylene which is cyclohexanediyl,(C₃-C₈)heterocycloalkylene which is piperidindiyl, pyrrolidindiyl, orazetidindiyl;

n is at each occurrence independently 0 or an integer from 1 to 3;

m is at each occurrence independently an integer from 1 to 3;

E is absent or is selected from —O—, —NR₇— which is —NH—, —NR₇—C(O)—which is —NH—C(O)—, —C(O)—NR₇— which is —C(O)—NH—, —C(O)—(CH₂)_(n)—O—which is —C(O)—CH₂—O—; —NR₇—C(O)—(CH₂)_(n)—O— which is —NH—C(O)—CH₂—O—;

G is arylene which is meta-phenylene or para-phenylene;

R₁ is selected from thiophenyl, cyclohexyl, cyclopentyl and phenyloptionally substituted by one or more group selected independently fromfluorine, methyl, ethyl and methoxy;

s is 0, 1 or 2

R₂ is a nitrogen containing group which may be selected from:

-   -   a group (a) which is —NR₃R₄ wherein R₃ and R₄ are methyl; and    -   a group (b) of formula J1, J2, J3, J4 or J5 wherein

R₅ is methyl or benzyl

and pharmaceutically acceptable salts or solvates thereof.

The present invention is also directed to a process for the preparationof the compounds of general formula I.

The present invention also provides pharmaceutical compositions ofcompounds of formula I alone or in combination with or in admixture withone or more pharmaceutically acceptable carriers and/or excipients.

The present invention also provides the use of compounds of formula Ifor preparing a medicament.

In a further aspect, the present invention provides the use of compoundsof formula I for the prevention and/or treatment of anybroncho-obstructive or inflammatory disease, preferably asthma orchronic bronchitis or chronic obstructive pulmonary disease (COPD).

In a further aspect, the present invention provides the use of compoundsof formula I for the manufacture of a medicament for the preventionand/or treatment of any broncho-obstructive or inflammatory disease,preferably asthma or chronic bronchitis or chronic obstructive pulmonarydisease (COPD).

The present invention further provides a method for prevention and/ortreatment of any broncho-obstructive or inflammatory disease, preferablyasthma or chronic bronchitis or chronic obstructive pulmonary disease(COPD), which comprises administering to a subject in need thereof atherapeutically effective amount of a compound of general formula I.

The present invention also provides pharmaceutical compositions suitablefor administration by inhalation.

Inhalable preparations include inhalable powders, propellant-containingmetering aerosols or propellant-free inhalable formulations.

The present invention is also directed to a device which may be asingle- or multi-dose dry powder inhaler, a metered dose inhaler and asoft mist nebulizer comprising the compounds of formula I.

The present invention is also directed to a kit comprising thepharmaceutical compositions of compounds of formula I alone or incombination with or in admixture with one or more pharmaceuticallyacceptable carriers and/or excipients and a device which may be asingle- or multi-dose dry powder inhaler, a metered dose inhaler and asoft mist nebulizer comprising the said combination or admixture.

According to specific embodiments, the present invention provides thecompounds reported below:

No. Structure Name  1 (1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-((5-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)pentyl)oxy)phenyl)-2-phenylacetate  2 (1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-((5-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)pentyl)oxy)phenyl)-2-(p-tolyl)acetate  3 (1-benzylpiperidin-4-yl)methyl2-(4-fluorophenyl)-2-hydroxy-2-(3-((5-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)pentyl)oxy)phenyl)acetate  4(1-benzylpiperidin-4-yl)methyl2-(3-fluorophenyl)-2-hydroxy-2-(3-((5-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)pentyl)oxy)phenyl)acetate  5(1-benzylpiperidin-4-yl)methyl 2-hydroxy-2-(3-((5-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)pentyl)oxy)phenyl)-2-(m-tolyl)acetate  6 (1-benzylpiperidin-4-yl)methyl2-(2-chlorophenyl)-2-hydroxy-2-(3-((5-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)pentyl)oxy)phenyl)acetate  7(1-benzylpiperidin-4-yl)methyl 2-hydroxy-2-(3-((5-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)pentyl)oxy)phenyl)-2-(o-tolyl)acetate  8 (1-benzylpiperidin-4-yl)methyl2-(2-ethylphenyl)-2-hydroxy-2-(3-((5-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)pentyl)oxy)phenyl)acetate  9(1-benzylpiperidin-4-yl)methyl 2-hydroxy-2-(3-((5-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)pentyl)oxy)phenyl)-2-(thiophen-2-yl)acetate  10 (1-benzylpiperidin-4-yl)methyl2-cyclohexyl-2-hydroxy-2-(3-((5-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)pentyl)oxy)phenyl)acetate  11(1-benzylpiperidin-4-yl)methyl2-(3-ethylphenyl)-2-hydroxy-2-(3-((5-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)pentyl)oxy)phenyl)acetate  12 (R)-quinuclidin-3-yl2-hydroxy-2-(3-((5-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)pentyl)oxy)phenyl)-2-(4-methoxyphenyl)acetate  12A (R)-quinuclidin-3-yl2-cyclopentyl-2-hydroxy-2-(3-((5-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)pentyl)oxy)phenyl)acetate  13(S)-(1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-((5-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)pentyl)oxy)phenyl)-2-phenylacetate  14 (R)-(1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-((5-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)pentyl)oxy)phenyl)-2-phenylacetate  15 (R)-quinuclidin-3-yl2-hydroxy-2-(3-((5-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)pentyl)oxy)phenyl)-2-phenylacetate 16 (R)-(R)-quinuclidin-3-yl2-hydroxy-2-(3-((5-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)pentyl)oxy)phenyl)-2-phenylacetate 17 (S)-2-(dimethylamino)ethyl 2-hydroxy-2-(3-((5-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)pentyl)oxy)phenyl)-2-phenylacetate  18 (R)-2-(dimethylamino)ethyl2-hydroxy-2-(3-((5-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)pentyl)oxy)phenyl)-2-phenylacetate  19 (S)-(R)-1-methylpyrrolidin-3-yl2-hydroxy-2-(3-((5-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)pentyl)oxy)phenyl)-2-phenylacetate  20 (R)-(R)-1-methylpyrrolidin-3-yl2-hydroxy-2-(3-((5-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)pentyl)oxy)phenyl)-2-phenylacetate  21 (S)-1-methylpiperidin-4-yl2-hydroxy-2-(3-((5-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)pentyl)oxy)phenyl)-2-phenylacetate  22 (R)-1-methylpiperidin-4-yl2-hydroxy-2-(3-((5-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)pentyl)oxy)phenyl)-2-phenylacetate  23 (S)-(1-methylpiperidin-4-yl)methyl2-hydroxy-2-(3-((5-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)pentyl)oxy)phenyl)-2-phenylacetate  24 (R)-(1-methylpiperidin-4-yl)methyl2-hydroxy-2-(3-((5-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)pentyl)oxy)phenyl)-2-phenylacetate  25 (S)-(R)-1-methylpiperidin-3-yl2-hydroxy-2-(3-((5-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)pentyl)oxy)phenyl)-2-phenylacetate  26 (S)-1-methylazetidin-3-yl2-hydroxy-2-(3-((5-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)pentyl)oxy)phenyl)-2-phenylacetate  27 (R)-(1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-((6-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)hexyl)oxy)phenyl)-2-phenylacetate  28 (S)-(1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-((7-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)heptyl)oxy)phenyl)-2-phenylacetate  29 (S)-(1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-((6-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)hexyl)oxy)phenyl)-2-phenylacetate  30 (S)-(1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-((8-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)octyl)oxy)phenyl)-2-phenylacetate  31 (S)-(1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-((1-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzoyl)piperidin-4-yl)methoxy)phenyl)-2-phenylacetate 32 (S)-(1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-(3-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzamido)propoxy)phenyl)-2-phenylacetate  32A(S)-(1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-(3-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-3-methoxybenzamido)propoxy)phenyl)-2-phenylacetate  32B(S)-(1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-(3-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-2-methoxybenzamido)propoxy)phenyl)-2-phenylacetate  32C(S)-(1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-(3-(6-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)nicotinamido)propoxy)phenyl)-2-phenylacetate  32D(S)-(1-benzylpiperidin-4-yl)methyl2-(3-(3-(3-ethoxy-4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzamido)propoxy)phenyl)-2-hydroxy-2-phenylacetate  32E (S)-(1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-(3-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-3-(trifluoromethoxy)benzamido)propoxy)phenyl)-2-phenylacetate  32F(S)-(1-benzylpiperidin-4-yl)methyl2-(3-(3-(2-fluoro-4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-3-methoxybenzamido)propoxy)phenyl)-2-hydroxy-2-phenylacetate  32G(S)-(1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-(3-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-3-isopropoxybenzamido)propoxy)phenyl)-2-phenylacetate  32H(S)-(1-benzylpiperidin-4-yl)methyl2-(3-(3-(2-chloro-4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzamido)propoxy)phenyl)-2-hydroxy-2-phenylacetate  32I (S)-(1-benzylpiperidin-4-yl)methyl2-(3-(3-(2-fluoro-4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-5-methoxybenzamido)propoxy)phenyl)-2-hydroxy-2-phenylacetate  32J(S)-(1-benzylpiperidin-4-yl)methyl2-(3-(3-(2-chloro-4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-5-methoxybenzamido)propoxy)phenyl)-2-hydroxy-2-phenylacetate  32K(S)-(1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-(3-(5-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)picolinamido)propoxy)phenyl)-2-phenylacetate  32L(S)-(1-benzylpiperidin-4-yl)methyl2-(3-(3-(2,3-difluoro-4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzamido)propoxy)phenyl)-2-hydroxy-2-phenylacetate  32M (S)-(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(3-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-3-(trifluoromethyl)benzamido)propoxy)phenyl)-2-phenylacetate  33(S)-(1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-((4-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-piperidine-1-carbonyl)benzyl)oxy)phenyl)-2-phenylacetate  33A(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-((4-(4-(2-(((R)-2-hydroxy-2-(4-hydroxy-6-oxo-5,6-dihydronaphthalen-1-yl)ethyl)amino)ethyl)piperidine-1-carbonyl)benzyl)oxy)phenyl)-2-phenylacetate  34(R)-(1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-(2-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzamido)ethoxy)phenyl)-2-phenylacetate  35(S)-(1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-((3-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-piperidine-1-carbonyl)benzyl)oxy)phenyl)-2-phenylacetate  36(S)-(1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-(2-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)piperidin-1-yl)-2-oxoethoxy)phenyl)-2-phenylacetate  36A(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)piperidin-1-yl)-2-oxoethoxy)phenyl)-2-phenylacetate  37(S)-(1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-(3-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzamido)propoxy)phenyl)-2-phenylacetate  38(S)-(1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-(2-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzamido)ethoxy)phenyl)-2-phenylacetate  39(1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-(2-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzamido)ethyl)phenyl)-2-phenylacetate  40(1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-(2-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzamido)ethyl)phenyl)-2-phenylacetate  41(S)-(1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-((1-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-benzoyl)azetidin-3-yl)methoxy)phenyl)-2-phenylacetate  42(S)-(1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-((1-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzoyl)azetidin-3-yl)methoxy)phenyl)-2-phenylacetate 42A (S)-(1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-(2-((4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-3-methoxyphenyl)amino)-2-oxoethoxy)phenyl)-2-phenylacetate  42B(1-benzylpiperidin-4-yl)methyl(S)-2-(3-(2-((2-fluoro-4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-5-methoxyphenyl)amino)-2-oxoethoxy)phenyl)-2-hydroxy-2-phenylacetate  42C(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-((4-((4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzamido)methyl)benzyl)oxy)phenyl)-2-phenylacetate 42D (1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-((4-((4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzamido)methyl)benzyl)oxy)phenyl)-2-phenylacetate 42E (1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-((4-((4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-2-methoxybenzamido)methyl)benzyl)oxy)phenyl)-2-phenylacetate  42F(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-((4-((4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-3-methoxybenzamido)methyl)benzyl)oxy)phenyl)-2-phenylacetate  43(S)-(1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-((4-((3-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)propyl)carbamoyl)benzyl)oxy)phenyl)-2-phenylacetate  44(R)-(1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-((4-((3-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)propyl)carbamoyl)benzyl)oxy)phenyl)-2-phenylacetate  45(S)-(1-benzylpiperidin-4-yl)methyl2-(3-((3-(benzyl(3-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)propyl)carbamoyl)benzyl)oxy)phenyl)-2-hydroxy-2-phenylacetate  46 (R)-quinuclidin-3-yl2-hydroxy-2-(3-(4-((5-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)pentyl)oxy)benzamido)phenyl)-2-phenylacetate  47 (1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-((4-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)butyl)carbamoyl)phenyl)-2-phenylacetate  48(R)-quinuclidin-3-yl2-hydroxy-2-(3-((4-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)butyl)carbamoyl)phenyl)-2-phenylacetate  49 (R)-1-methylpyrrolidin-3-yl2-hydroxy-2-(3-((4-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)butyl)carbamoyl)phenyl)-2-phenylacetate  50(1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-((3-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzamido)propyl)carbamoyl)phenyl)-2-phenylacetate 51 (1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(4-((5-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)pentyl)oxy)phenyl)-2-phenylacetate  52 (R)-quinuclidin-3-yl2-hydroxy-2-(4-((5-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)pentyl)oxy)phenyl)-2-phenylacetate 53 (1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(4-((4-((4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzamido)methyl)benzyl)oxy)phenyl)-2-phenylacetate 54 (1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-((((5-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)pentyl)oxy)carbonyl)amino)phenyl)-2-phenylacetate  55(R)-quinuclidin-3-yl2-hydroxy-2-(3-(5-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)pentanamido)phenyl)-2-phenylacetate 56 (1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-(3-(3-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzamido)propyl)ureido)phenyl)-2-phenylacetate 57 (1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-((2-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzamido)ethyl)amino)-2-oxoethoxy)phenyl)-2-phenylacetate  58 (1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(4-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzoyl)piperazin-1-yl)-2-oxoethoxy)phenyl)-2-phenylacetate  59 (1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(4-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzamido)piperidin-1-yl)-2-oxoethoxy)phenyl)-2-phenylacetate  60 (1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-((2-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzamido)ethyl)(methyl)amino)-2-oxoethoxy)phenyl)-2-phenylacetate  61 (1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(4-((4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzamido)methyl)piperidin-1-yl)-2-oxoethoxy)phenyl)-2-phenylacetate  62 (1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(((1R,4S)-4-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzamido)cyclohexyl)amino)-2-oxoethoxy)phenyl)-2-phenylacetate  63 (1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(((1R,3S)-3-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzamido)cyclobutyl)amino)-2-oxoethoxy)phenyl)-2-phenylacetate  64 (1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(9-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzoyl)-3,9-diazaspiro[5.5]undecan-3-yl)-2-oxoethoxy)phenyl)-2-phenylacetate  65(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-((1-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzoyl)piperidin-4-yl)amino)-2-oxoethoxy)phenyl)-2-phenylacetate  66 (1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-((1-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzoyl)azetidin-3-yl)amino)-2-oxoethoxy)phenyl)-2-phenylacetate  67 (1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(3-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzamido)azetidin-1-yl)-2-oxoethoxy)phenyl)-2-phenylacetate  68 (1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(((R)-1-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzoyl)pyrrolidin-3-yl)amino)-2-oxoethoxy)phenyl)-2-phenylacetate  69 (1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(((S)-1-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzoyl)piperidin-3-yl)amino)-2-oxoethoxy)phenyl)-2-phenylacetate  70 (1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(((S)-1-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzoyl)pyrrolidin-3-yl)amino)-2-oxoethoxy)phenyl)-2-phenylacetate  71 (1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(((R)-1-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzoyl)piperidin-3-yl)amino)-2-oxoethoxy)phenyl)-2-phenylacetate  72 (1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-((S)-3-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzamido)piperidin-1-yl)-2-oxoethoxy)phenyl)-2-phenylacetate  73 (1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-((S)-3-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzamido)pyrrolidin-1-yl)-2-oxoethoxy)phenyl)-2-phenylacetate  74 (1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-((3aR,6aR)-5-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzoyl)hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)-2-oxoethoxy)phenyl)-2-phenylacetate  75 (1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-((R)-3-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzamido)piperidin-1-yl)-2-oxoethoxy)phenyl)-2-phenylacetate  76 (1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-((R)-3-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzamido)pyrrolidin-1-yl)-2-oxoethoxy)phenyl)-2-phenylacetate  77 (1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-((3aS,6aS)-5-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzoyl)hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)-2-oxoethoxy)phenyl)-2-phenylacetate  78 (1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-((1-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-3-methoxybenzoyl)azetidin-3-yl)amino)-2-oxoethoxy)phenyl)-2-phenylacetate 79 (1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(9-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-3-methoxybenzoyl)-3,9-diazaspiro[5.5]undecan-3-yl)-2-oxoethoxy)phenyl)-2-phenylacetate  80 (1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(4-((4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-3-methoxybenzamido)methyl)piperidin-1-yl)-2-oxoethoxy)phenyl)-2-phenylacetate  81 (1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(9-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-2-methoxybenzoyl)-3,9-diazaspiro[5.5]undecan-3-yl)-2-oxoethoxy)phenyl)-2-phenylacetate  82 (1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-((1-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-2-methoxybenzoyl)azetidin-3-yl)amino)-2-oxoethoxy)phenyl)-2-phenylacetate 83 (1-benzylpiperidin-4-yl)methyl(S)-2-(3-(2-(ethyl(2-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzamido)ethyl)amino)-2-oxoethoxy)phenyl)-2-hydroxy-2-phenylacetate  84 (1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-((2-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzamido)ethyl)(methyl)amino)-2-oxoethoxy)phenyl)-2-phenylacetate  85 (1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-((3-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzamido)propyl)amino)-2-oxoethoxy)phenyl)-2-phenylacetate  86 (1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(4-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzoyl)piperazin-1-yl)-2-oxoethoxy)phenyl)-2-phenylacetate  87 (1-benzylpiperidin-4-yl)methyl(S)-2-(3-(2-(benzyl(2-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzamido)ethyl)amino)-2-oxoethoxy)phenyl)-2-hydroxy-2-phenylacetate  88 (1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(((1R,3S)-3-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzamido)cyclobutyl)amino)-2-oxoethoxy)phenyl)-2-phenylacetate  89 (1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(4-((4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzamido)methyl)piperidin-1-yl)-2-oxoethoxy)phenyl)-2-phenylacetate  90 (1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(((1R,4S)-4-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzamido)cyclohexyl)amino)-2-oxoethoxy)phenyl)-2-phenylacetate  91 (1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-((1-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzoyl)piperidin-4-yl)amino)-2-oxoethoxy)phenyl)-2-phenylacetate  92 (1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(4-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzamido)piperidin-1-yl)-2-oxoethoxy)phenyl)-2-phenylacetate  93 (1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(6-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzoyl)-2,6-diazaspiro[3.3]heptan-2-yl)-2-oxoethoxy)phenyl)-2-phenylacetate  94 (1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(7-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzoyl)-2,7-diazaspiro[3.5]nonan-2-yl)-2-oxoethoxy)phenyl)-2-phenylacetate  95 (1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(9-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzoyl)-3,9-diazaspiro[5.5]undecan-3-yl)-2-oxoethoxy)phenyl)-2-phenylacetate  96 (1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(2-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzoyl)-2,7-diazaspiro[3.5]nonan-7-yl)-2-oxoethoxy)phenyl)-2-phenylacetate  97 (1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(((1-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzoyl)piperidin-4-yl)methyl)amino)-2-oxoethoxy)phenyl)-2-phenylacetate  98 (1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(6-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzoyl)-2,6-diazaspiro[3.5]nonan-2-yl)-2-oxoethoxy)phenyl)-2-phenylacetate  99 (1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(9-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzoyl)-2,9-diazaspiro[5.5]undecan-2-yl)-2-oxoethoxy)phenyl)-2-phenylacetate 100 (1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(9-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzoyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)-2-oxoethoxy)phenyl)-2-phenylacetate 101 (1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-((1-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzoyl)azetidin-3-yl)amino)-2-oxoethoxy)phenyl)-2-phenylacetate 102 (1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(3-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzamido)azetidin-1-yl)-2-oxoethoxy)phenyl)-2-phenylacetate 103 (1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-((2-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzamido)ethyl)amino)-2-oxoethoxy)phenyl)-2-phenylacetate 104 (1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(((R)-1-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzoyl)pyrrolidin-3-yl)amino)-2-oxoethoxy)phenyl)-2-phenylacetate 105 (1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(((R)-1-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzoyl)piperidin-3-yl)amino)-2-oxoethoxy)phenyl)-2-phenylacetate 106 (1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(((S)-1-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzoyl)piperidin-3-yl)amino)-2-oxoethoxy)phenyl)-2-phenylacetate 107 (1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(((S)-1-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzoyl)pyrrolidin-3-yl)amino)-2-oxoethoxy)phenyl)-2-phenylacetate 108 (1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-((S)-3-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzamido)piperidin-1-yl)-2-oxoethoxy)phenyl)-2-phenylacetate 109 (1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-((S)-3-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzamido)pyrrolidin-1-yl)-2-oxoethoxy)phenyl)-2-phenylacetate 110 (1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-((R)-3-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzamido)pyrrolidin-1-yl)-2-oxoethoxy)phenyl)-2-phenylacetate 111 (1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-((3aR,6aR)-1-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzoyl)hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)-2-oxoethoxy)phenyl)-2-phenylacetate 112 (1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-((3aS,6aS)-1-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzoyl)hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)-2-oxoethoxy)phenyl)-2-phenylacetate 113 (1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-((R)-3-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzamido)piperidin-1-yl)-2-oxoethoxy)phenyl)-2-phenylacetate 114 (1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-((4-(((1R,3S)-3-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzamido)cyclobutyl)carbamoyl)benzyl)oxy)phenyl)-2-phenylacetate 115 (1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-((4-(9-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzoyl)-3,9-diazaspiro[5,5]undecane-3-carbonyl)benzyl)oxy)phenyl)-2-phenylacetate 116(1-benzylpiperidin-4-yl)methyl (S)-2-hydroxy-2-(3-((4-(6-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzoyl)-2,6-diazaspiro[3.3]heptane-2-carbonyl)benzyl)oxy)phenyl)-2-phenylacetate 117(1-benzylpiperidin-4-yl)methyl (S)-2-hydroxy-2-(3-((4-(7-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzoyl)-2,7-diazaspiro[3.5]nonane-2-carbonyl)benzyl)oxy)phenyl)-2-phenylacetate 118(1-benzylpiperidin-4-yl)methyl (S)-2-hydroxy-2-(3-((4-(4-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzoyl)piperazine-1-carbonyl)benzyl)oxy)phenyl)-2-phenylacetate 119 (1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-((4-(2-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzoyl)-2,7-diazaspiro[3.5]nonane-7-carbonyl)benzyl)oxy)phenyl)-2-phenylacetate 120(1-benzylpiperidin-4-yl)methyl (S)-2-hydroxy-2-(3-((4-(6-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzoyl)-2,6-diazaspiro[3.5]nonane-2-carbonyl)benzyl)oxy)phenyl)-2-phenylacetate 121(1-benzylpiperidin-4-yl)methyl (S)-2-hydroxy-2-(3-((4-(9-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzoyl)-1-oxa-4,9-diazaspiro[5.5]undecane-4-carbonyl)benzyl)oxy)phenyl)-2-phenylacetate 122(1-benzylpiperidin-4-yl)methyl (S)-2-hydroxy-2-(3-((4-(9-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzoyl)-2,9-diazaspiro[5.5]undecane-2-carbonyl)benzyl)oxy)phenyl)-2-phenylacetate 123(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-((4-(((1R,3S)-3-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzamido)cyclobutyl)carbamoyl)benzyl)oxy)phenyl)-2-phenylacetate 124 (1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-((4-(((1R,3S)-3-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-3-methoxybenzamido)cyclobutyl)carbamoyl)benzyl)oxy)phenyl)-2-phenylacetate125 (1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-((4-((2-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzamido)ethyl)carbamoyl)benzyl)oxy)phenyl)-2-phenylacetate 126 (1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-((4-((2-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-3-methoxybenzamido)ethyl)carbamoyl)benzyl)oxy)phenyl)-2-phenylacetate 127(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(((1R,3S)-3-(3-hydroxy-4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzamido)cyclobutyl)amino)-2-oxoethoxy)phenyl)-2-phenylacetate 128 (S)-(1-benzylpiperidin-4-yl)methyl2-(3-(2-(((1R,3S)-3-(2-fluoro-4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzamido)cyclobutyl)amino)-2-oxoethoxy)phenyl)-2-hydroxy-2-phenylacetate 129 (S)-(1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-(2-(((1R,3S)-3-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-3-methylbenzamido)cyclobutyl)amino)-2-oxoethoxy)phenyl)-2-phenylacetate130 (S)-(1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-(2-(((1R,3S)-3-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-2-methoxybenzamido)cyclobutyl)amino)-2-oxoethoxy)phenyl)-2-phenylacetate131 (S)-(1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-(2-(((1R,3S)-3-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-3-methoxybenzamido)cyclobutyl)amino)-2-oxoethoxy)phenyl)-2-phenylacetate132 (1-benzylpiperidin-4-yl)methyl(S)-2-(3-(2-(((1R,3S)-3-(3-fluoro-4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzamido)cyclobutyl)amino)-2-oxoethoxy)phenyl)-2-hydroxy-2-phenylacetate 133 (1-benzylpiperidin-4-yl)methyl(S)-2-(3-(2-(((1R,3S)-3-(2-chloro-4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzamido)cyclobutyl)amino)-2-oxoethoxy)phenyl)-2-hydroxy-2-phenylacetate 134 (1-benzylpiperidin-4-yl)methyl(S)-2-(3-(2-(((1R,3S)-3-(2,3-difluoro-4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzamido)cyclobutyl)amino)-2-oxoethoxy)phenyl)-2-hydroxy-2-phenylacetate 135 (1-benzylpiperidin-4-yl)methyl(S)-2-(3-(2-(((1R,3S)-3-(3-chloro-4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzamido)cyclobutyl)amino)-2-oxoethoxy)phenyl)-2-hydroxy-2-phenylacetate 136 (1-benzylpiperidin-4-yl)methyl(S)-2-(3-(2-(((1R,3S)-3-(2-bromo-4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzamido)cyclobutyl)amino)-2-oxoethoxy)phenyl)-2-hydroxy-2-phenylacetate 137 (1-benzylpiperidin-4-yl)methyl(S)-2-(3-(2-(((1R,3S)-3-(2-chloro-4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-5-methoxybenzamido)cyclobutyl)amino)-2-oxoethoxy)phenyl)-2-hydroxy-2-phenylacetate 138 (1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(((1R,3S)-3-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-3-(trifluoromethyl)benzamido)cyclobutyl)amino)-2-oxoethoxy)phenyl)-2-phenylacetate 139 (1-benzylpiperidin-4-yl)methyl(S)-2-(3-(2-(((1R,3S)-3-(2-fluoro-4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-3-methoxybenzamido)cyclobutyl)amino)-2-oxoethoxy)phenyl)-2-hydroxy-2-phenylacetate 140 (1-benzylpiperidin-4-yl)methyl(S)-2-(3-(2-(((1R,3S)-3-(3-ethoxy-4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzamido)cyclobutyl)amino)-2-oxoethoxy)phenyl)-2-hydroxy-2-phenylacetate 141 (1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(((1R,3S)-3-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-3-(trifluoromethoxy)benzamido)cyclobutyl)amino)-2-oxoethoxy)phenyl)-2-phenylacetate 142 (1-benzylpiperidin-4-yl)methyl(S)-2-(3-(2-(((1R,3S)-3-(2-fluoro-4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-5-methoxybenzamido)cyclobutyl)amino)-2-oxoethoxy)phenyl)-2-hydroxy-2-phenylacetate 143 (1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(((1R,3S)-3-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-3-isopropoxybenzamido)cyclobutyl)amino)-2-oxoethoxy)phenyl)-2-phenylacetate144 (1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(((1R,3S)-3-(5-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)picolinamido)cyclobutyl)amino)-2-oxoethoxy)phenyl)-2-phenylacetate 145 (1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(((1R,3S)-3-(6-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)nicotinamido)cyclobutyl)amino)-2-oxoethoxy)phenyl)-2-phenylacetate 146 (1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(((1R,3S)-3-(2-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)phenyl)acetamido)cyclobutyl)amino)-2-oxoethoxy)phenyl)-2-phenylacetate 147 (1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(3-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)piperidine-1-carbonyl)azetidin-1-yl)-2-oxoethoxy)phenyl)-2-phenylacetate 148(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(4-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)piperidine-1-carbonyl)piperidin-1-yl)-2-oxoethoxy)phenyl)-2-phenylacetate 149(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(((1R,4S)-4-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)piperidine-1-carbonyl)cyclohexyl)amino)-2-oxoethoxy)phenyl)-2-phenylacetate 150 (1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-((2-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)piperidin-1-yl)-2-oxoethyl)amino)-2-oxoethoxy)phenyl)-2-phenylacetate 151(1-benzylpiperidin-4-yl)methyl (S)-2-hydroxy-2-(3-((1-(1-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzoyl)piperidine-4-carbonyl)piperidin-4-yl)methoxy)phenyl)-2-phenylacetate 152 (1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-((1-((4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzoyl)glycyl)piperidin-4-yl)methoxy)phenyl)-2-phenylacetate 153 (1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-((1-((4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-3-methoxybenzoyl)glycyl)piperidin-4-yl)methoxy)phenyl)-2-phenylacetate 154(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-((1-((4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzoyl)glycyl)piperidin-4-yl)methoxy)phenyl)-2-phenylacetate 155 (1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-((1-((4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-2-methoxybenzoyl)glycyl)piperidin-4-yl)methoxy)phenyl)-2-phenylacetate 156(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-((1-(5-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)piperidine-1-carbonyl)thiophene-2-carbonyl)piperidin-4-yl)methoxy)phenyl)-2-phenylacetate 157 (1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-((1-((1R,4S)-4-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)piperidine-1-carbonyl)cyclohexane-1-carbonyl)piperidin-4-yl)methoxy)phenyl)-2-phenylacetate 1581-benzylpiperidin-4-yl (S)-2-hydroxy-2-(3-(3-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzamido)propoxy)phenyl)-2-phenylacetate 159((R)-1-benzylpyrrolidin-3-yl)methyl (S)-2-hydroxy-2-(3-(3-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzamido)propoxy)phenyl)-2-phenylacetate 160((S)-1-benzylpyrrolidin-3-yl)methyl (S)-2-hydroxy-2-(3-(3-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzamido)propoxy)phenyl)-2-phenylacetate 161(1-cyclobutylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(3-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzamido)propoxy)phenyl)-2-phenylacetate 162(1-methylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(3-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzamido)propoxy)phenyl)-2-phenylacetate 163(R)-1-benzylpyrrolidin-3-yl(S)-2-hydroxy-2-(3-(3-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzamido)propoxy)phenyl)-2-phenylacetate 164(S)-1-benzylpyrrolidin-3-yl(S)-2-hydroxy-2-(3-(3-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzamido)propoxy)phenyl)-2-phenylacetate 1651-benzylazetidin-3-yl (S)-2-hydroxy-2-(3-(3-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzamido)propoxy)phenyl)-2-phenylacetate 1661-benzylpiperidin-4-yl(S)-2-hydroxy-2-(3-((4-((3-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)phenyl)ureido)methyl)benzyl)oxy)phenyl)-2-phenylacetate 167 1-benzylpiperidin-4-yl(S)-2-hydroxy-2-(3-((4-((3-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-3-methoxyphenyl)ureido)methyl)benzyl)oxy)phenyl)-2-phenylacetate 1681-benzylpiperidin-4-yl(S)-2-hydroxy-2-(3-((4-((3-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-2-methoxyphenyl)ureido)methyl)benzyl)oxy)phenyl)-2-phenylacetate

The compounds of the present invention can be prepared from readilyavailable starting materials using the following general methods andprocedures or by using other information readily available to those ofordinary skill in the art. Although a particular embodiment of thepresent invention may be shown or described herein, those skilled in theart will recognize that all embodiments or aspects of the presentinvention can be prepared using the methods described herein or by usingother methods, reagents and starting materials known to those skilled inthe art. It will also be appreciated that where typical or preferredprocess conditions (i.e., reaction temperatures, times, mole ratios ofreactants, solvents, pressures, etc.) are given, other processconditions can also be used unless otherwise stated. While the optimumreaction conditions may vary depending on the particular reactants orsolvent used, such conditions can be readily determined by one skilledin the art by routine optimisation procedures.

Compounds of general formula I may be prepared according to thefollowing synthetic Scheme.

General Procedure for the Preparation of Compounds of Formula I

Compounds of general formula I are compounds in which Y is a divalentgroup of formula Y1 or Y2. Although groups Y1 and Y2 are different theapproach to be considered for the synthesis of compounds of formula I inwhich Y is Y1 or Y2 is similar and mainly depends on the functionalgroup present in the linker Y. It is evident for a person skilled in theart that the following synthesis described for Y2 can be extended withminor modification to Y1.

The compounds of general formula XII represent compounds wherein A1 isalkylene substituted with oxo, leading to an aldehyde or ketoneprotected as cyclic acetal. The cyclic acetal-protecting group (PG) canbe removed leading to a compound of general formula XIII.

The synthesis of compounds of general formula I may require theprotection of potential reactive functionalities in addition to thosemethods already described. In such a case, examples of compatibleprotecting groups (PG) and their particular methods of protection anddeprotection are described in “Protecting groups in organic Synthesis”by T. W. Green and P. Wutz (Wiley-Interscience publication, 1999), whichis incorporated herein by reference in its entirety. Compounds ofgeneral formula I can be prepared for example by reaction of a compoundof general formula XIII with a compound of general formula XIV. Thisreductive amination reaction can be performed following severaldifferent protocols described in the literature and well known for thoseskilled in the art. For example, it can be performed in solvent such asmethanol, ethanol, tetrahydrofuran (THF) or dichloromethane (DCM) usinga reducing agent such as NaBH₄, NaCNBH₃ or NaB(AcO)₃H. It could beuseful to pre-form the imine before adding the reducing agent. Thereaction proceeds smoothly at room temperature (RT) over 1 to 12 hours.

The intermediate of general formula XII can be easily prepared byreaction of a compound of general formula XI with a compound of formulaHO—(CH₂)_(s)—R₂ under the well-known condensation conditions for thepreparation of esters. The reaction occurs smoothly in an aprotic polarsolvent such as DCM, THF or DMF at room or higher temperature in thepresence of a condensing agent such as for example EDC, DCC, HATU.Alternatively the acid XI can be converted into the correspondingchloride (e.g. with COCl₂ in DMC) or imidazolide (with CDI in DCM orDMF) and then treated with HO—(CH₂)_(s)—R₂.

Intermediate XI can be easily obtained by saponification of ester VIIIusing alkaline hydroxides in polar solvent, such as MeOH, EtOH, and THFmixed with water in a suitable ratio. The reaction occurs at RT, buthigher temperature can speed the reaction up that can complete in a timeranging from 30 minutes to overnight.

Synthesis of compound of formula VIII can be achieved in many differentways, all depending on functional groups present in G. For example, itcan be obtained by reaction of a compound of formula VII with a compoundof formula III. In the case n is greater than zero and E is —O— thereaction is the well-known alkylation of phenols. The leaving group LGcan be easily displaced reacting the two compounds in a polar solventsuch as for example, but not limited to, ACN or DMF, for one or morehours at room or higher temperature.

The same reaction conditions can be used for the conversion of acompound of formula II into IV using a compound of formula III.

Compound of general formula VII can be obtained using the known additionof Grignard reagent (or other metal derivatives) to keto-containingcompounds such as VI or II. The selection of one of the two possiblereactions depends on the availability of suitable Grignard's reagent ora precursor for its generation. The conversion of VI to VII can beperformed in a solvent such as Et₂O or THF at a temperature below 0° C.The reaction is normally smooth and completes over a period ranging fromone to overnight standing at room temperature. The same reactionconditions can be used for the reaction of a compound of formula IV witha compound of formula V to give a compound of formula VIII.

In another embodiment of the present invention, intermediate VIII can beused for the preparation of I using a different approach.

First VIII is deprotected to give an aldehyde that can be easily reactedwith a compound of formula XIV under the reductive amination conditionsdescribed above for the conversion of XIII into I. The ester of formulaIX obtained is then hydrolysed, under acidic or basic aqueous conditionas described for the preparation of XI, to give X that can be reactedunder ester formation condition with a compound of formulaHO—(CH₂)_(s)—R₂.

It is clear to a person skilled in the art that the presence of OH andNH moiety, for example in a compound of formula X, can affect theformation of the ester I as these functional groups can compete with theOH in HO—(CH₂)_(s)—R₂. For this reason, it is worth consideringperforming such described reaction, for the conversion of X into I,using an intermediate in which the OH and NH are protected with suitableprotecting group. For the purpose silyl ethers for the OH and carbamatesfor the NH are well known protecting groups, whose selection should notbe limited to them as it often depends on the complexity of the moleculeand the presence of other functional groups in Y that can be notcompatible with the reaction conditions required for introduction orremoval of protecting groups.

A similar consideration can be done for the moiety Q that contains aphenolic OH. In addition, in this case its reactivity can suggests itsprotection to avoid any competitive reaction and formation ofby-products. Benzyl is a suitable protecting group. The specificsequence of reaction for the preparation of I might be different fromcase to case, those skilled in the art will readily recognize theappropriate sequence, that must be evaluated considering the structureof linker Y.

In another embodiment of the present invention, compounds of generalformula I featuring an ester moiety in the linker Y, can be prepared bytreating a compound of general formula XXVIII with a compound of generalformula XXIX, wherein A2 is functionalized with OH, under thecondensation reaction condition for the preparation of esters. It ispossible prepare a compound of general formula I, wherein C is equal toC1, reacting a compound of general formula XXVIII with a compound XXIXwherein A2 is substituted with —NR₇ under the well-known reactionconditions for the preparation of amide starting from carboxylic acidand amines. Using a similar approach it is possible to synthesize acompound of formula I wherein C has one of the other meanings cited,using intermediates featuring the correct functional groups that canreact together to form one of meaning of C.

Compound of formula XXVIII can be obtained by a reaction of a compoundof formula XXV with a suitable intermediate whose formula depends on thestructure of the linker Y. An example that must not be considered aslimiting the scope of the description, is the preparation of a compoundof formula I wherein E is —O— which can be easily obtained treating acompound of formula XXV with a compound of formula XXVII where LG isleaving group such as chlorine, bromine or sulfonates. The reaction ofalkylation can be performed in polar solvents such as DCM, ACN or DMF atroom or higher temperature in the presence of base that can catalyze thereaction.

Compound of formula XXV can be obtained from XXX via a reaction forester formation already described for the conversion of XI into XII.Compound XXX is easily obtained from compound of formula VII by mean ofa standard reaction for the hydrolysis of esters.

Compounds of general formula VII, XXX and XXV are all suitableintermediates for the preparation of single stereoisomers of compound offormula I. For example, the mixtures of isomers of these threeintermediates can be separated by mean of chiral chromatographicseparation. In case, for example, R2 is enantiomerically pure J1, J2 orJ5, a compound of formula XXV is a mixture of diastereoisomers that canbe separated by mean of a normal chromatographic separation.

The absolute configuration of the stereogenic centre present in VII isconserved unmodified within the synthetic pathway applied for theconversion of VII into the final compound of formula I.

In another embodiment of the present invention, compounds of generalformula I can be prepared following a different synthetic approach inwhich a compound of general formula XX is reacted with a compound offormula XXII under the transition metal catalyzed cross-couplingreaction conditions, followed by reduction of the double bond —(CH)₂—,leading to a compound of formula I wherein n=2. Alternatively, it can beprepared by reaction of a compound of formula XVII with a compound offormula XXIII under the condition described above for the reaction of acompound of formula II with a compound of formula III.

Intermediates of formula XX and XVII can be prepared by reaction ofcompound of formula XIV under reductive amination conditions, describedabove for the reaction of compound of formula XIII with XIV, startingfrom compound of formula XIX and XVIII respectively. Alternatively,compounds of formula XX and XVII can be prepared by alkylation ofcompound XIV with compound of formula XXI and XX respectively underalkylation condition described above for the preparation of compoundVIII by reaction of compound VII with compound III.

Compounds of general formula XIV can be obtained by simple reduction ofthe azide of formula XV. The reaction can be accomplished by mean of acatalytic hydrogenation in the presence Palladium catalyst. The reactionoccurs, in polar solvent such as methanol or ethanol, under hydrogenatmosphere or under hydrogen transfer condition, using for example1,4-cyclohexadiene or 1-methyl1,4-cyclohexadiene as source of hydrogen.The reaction proceeds at room temperature. In case it is performed underhydrogen transfer conditions higher temperature can be required.Alternatively, the conversion can be accomplished under Staudingerreaction conditions.

The azide XV can be easily prepared from XXIV by the well-knownnucleophilic substitution of alkyl bromide with alkaline azide. Thereaction proceeds at a temperature ranging from 50 to 80° C. and in apolar solvent such as for example DMF of NMP and can be accelerated bythe presence of alkaline iodide.

In another embodiment of the present invention, compounds of generalformula XVII can be prepared by reacting an intermediate of generalformula XXIV with an amine of general formula XXV. This reaction is acommon alkylation of amine in which the leaving group LG (normallychlorine, bromine or sulphate) is displaced by a nucleophile like theamine XXV as such or protected at the aminic moiety. Several methods toperform a reaction that normally occurs in a polar solvent at atemperature higher than room temperature are described in theliterature.

It is apparent for those skilled in the art that compounds of generalformula I wherein s is 0 and R2 is J1, J2, or J5 contain threestereogenic centres, as indicated below (wherein e.g. J=J2) with thesymbol *. This means that the structure of formula I is characterized bydifferent stereoisomers.

Each diastereoisomer can be obtained theoretically by chromatographicseparation of the mixture obtained by reacting racemic mixtures of therequired intermediates. It is clear that this approach it is notconvenient and that it can be used only for the separation of mixturescontaining few diastereoisomers.

In a more convenient approach, the synthesis of each single stereoisomercan be accomplished using, in the reactions described above, onlyenantiomerically pure intermediates.

The enantiomerically pure alcohol required for the preparation ofcompounds of general formula I wherein R2 is J1, J2 or J5 arecommercially available.

The preparation of single enantiomerically pure compounds of generalformula XXIV wherein LG is bromine are described in WO2005/092861 (citedby WO2007/107228), both of which are incorporated herein by reference intheir entireties.

The present invention also provides pharmaceutical compositions ofcompounds of formula I in admixture with one or more pharmaceuticallyacceptable carriers, for example those described in Remington'sPharmaceutical Sciences Handbook, XVII Ed., Mack Pub., N.Y., U.S.A.,which is incorporated herein by reference in its entirety

Administration of the compounds of the present invention may beaccomplished according to patient needs, for example, orally, nasally,parenterally (subcutaneously, intravenously, intramuscularly,intrasternally and by infusion), by inhalation, rectally, vaginally,topically, locally, transdermally, and by ocular administration.

Various solid oral dosage forms can be used for administering compoundsof the invention including such solid forms as tablets, gelcaps,capsules, caplets, granules, lozenges and bulk powders. The compounds ofthe present invention can be administered alone or combined with variouspharmaceutically acceptable carriers, diluents (such as sucrose,mannitol, lactose, starches) and known excipients, including suspendingagents, solubilizers, buffering agents, binders, disintegrants,preservatives, colorants, flavorants, lubricants and the like. Timerelease capsules, tablets and gels are also advantageous inadministering the compounds of the present invention.

Various liquid oral dosage forms can also be used for administeringcompounds of the present invention, including aqueous and non-aqueoussolutions, emulsions, suspensions, syrups, and elixirs. Such dosageforms can also contain suitable known inert diluents such as water andsuitable known excipients such as preservatives, wetting agents,sweeteners, flavorants, as well as agents for emulsifying and/orsuspending the compounds of the invention. The compounds of the presentinvention may be injected, for example, intravenously, in the form of anisotonic sterile solution. Other preparations are also possible.

Suppositories for rectal administration of the compounds of the presentinvention can be prepared by mixing the compound with a suitableexcipient such as cocoa butter, salicylates and polyethylene glycols.

Formulations for vaginal administration can be in the form of cream,gel, paste, foam, or spray formula containing, in addition to the activeingredient, such as suitable carriers, are also known.

For topical administration the pharmaceutical composition can be in theform of creams, ointments, liniments, lotions, emulsions, suspensions,gels, solutions, pastes, powders, sprays, and drops suitable foradministration to the skin, eye, ear, or nose. Topical administrationmay also involve transdermal administration via means such astransdermal patches.

For the treatment of the diseases of the respiratory tract, thecompounds according to the invention are preferably administered byinhalation.

Inhalable preparations include inhalable powders, propellant-containingmetering aerosols or propellant-free inhalable formulations.

For administration as a dry powder, single- or multi-dose inhalers knownfrom the prior art may be utilized. In that case the powder may befilled in gelatine, plastic or other capsules, cartridges or blisterpacks or in a reservoir.

A diluent or carrier, generally non-toxic and chemically inert to thecompounds of the present invention, e.g. lactose or any other additivesuitable for improving the respirable fraction may be added to thepowdered compounds of the invention.

Inhalation aerosols containing propellant gas such as hydrofluoroalkanesmay contain the compounds of the present invention either in solution orin dispersed form. The propellant-driven formulations may also containother ingredients such as co-solvents, stabilizers and optionally otherexcipients.

The propellant-free inhalable formulations comprising the compounds ofthe present invention may be in form of solutions or suspensions in anaqueous, alcoholic or hydroalcoholic medium and they may be delivered byjet or ultrasonic nebulizers known from the prior art or by soft-mistnebulizers such as Respimat®.

The compounds of the present invention may be administered as the soleactive agent or in combination with other pharmaceutical activeingredients including those currently used in the treatment ofrespiratory disorders, e.g, corticosteroids, P38 MAP kinase inhibitors,IKK2, FINE inhibitors, PDE4 inhibitors, leukotriene modulators, NSAIDsand mucus regulators.

The dosages of the compounds of the present invention depend upon avariety of factors including the particular disease to be treated, theseverity of the symptoms, the route of administration, the frequency ofthe dosage interval, the particular compound utilized, the efficacy,toxicology profile, and pharmacokinetic profile of the compound.

Advantageously, the compounds of formula I can be administered forexample, at a dosage of 0.001 to 1000 mg/day, preferably 0.1 to 500mg/day.

When the compounds of formula I are administered by inhalation route,they are preferably given at a dosage of 0.001 to 500 mg/day, preferably0.1 to 200 mg/day.

The compounds of formula I may be administered for the prevention and/ortreatment of broncho-obstructive or inflammatory diseases, such asasthma, chronic bronchitis, chronic obstructive pulmonary disease(COPD), bronchial hyperreactivity, cough, emphysema or rhinitis;urological disorders such as urinary incontinence, pollakiuria,cystospasm, chronic cystitis and overactive bladder (OAB);gastrointestinal disorders such as bowel syndrome, spastic colitis,diverticulitis, peptic ulceration, gastrointestinal motility or gastricacid secretion; dry mouth; mydriasis, tachycardia; ophthalmicinterventions cardiovascular disorders such as vagally induced sinusbradycardia.

Other features of the invention will become apparent in the course ofthe following descriptions of exemplary embodiments which are given forillustration of the invention and are not intended to be limitingthereof.

EXAMPLES

The intermediate compounds for the synthesis of final compounds ofgeneral formula (I) were obtained through the preparations herebelowdescribed.

Preparation of Intermediates and Examples

Chemical Names of the compounds were generated with Structure To NameEnterprise 10.0 CambridgeSoft for all final compounds names or withChemDraw Professional 15 for intermediates names.

ABBREVIATIONS

Et₂O=diethyl ether;Et₃N=triethyl amine;DCE=1,2-dichloroethane;TEA=tryethyl amine;DCC=N,N′-dicyclohexylcarbodiimide;HOBt=hydroxybenzotriazole;HATU=(dimethylamino)-N,N-dimethyl(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methaniminiumhexafluorophosphate;EDC=1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride;DMAP=4-dimethylaminopyridine;DMF=dimethylformamide;EtOAc=ethyl acetate;RT=room temperature;THF=tetrahydrofuran;DCM=dichloromethane;MeOH=methyl alcohol;EtOH=ethylic alcohol;LHMDS=lithium bis(trimethylsilyl)amide;m-CPBA=meta-Chloroperoxybenzoic acid;TFA=trifluoroacetic acid;LC-MS=liquid chromatography/mass spectrometry;HPLC=high pressure liquid chromatography;MPLC=medium pressure liquid chromatography;SFC=supercritical fluid chromatography

General Experimental Details. NMR Characterization:

¹H-NMR spectra were performed on a Varian MR-400 spectrometer operatingat 400 MHz (proton frequency), equipped with: a self-shielded z-gradientcoil 5 mm 1H/nX broad band probehead for reverse detection, deuteriumdigital lock channel unit, quadrature digital detection unit withtransmitter offset frequency shift.

Alternatively a Bruker instrument was used (either Bruker Avance 400 MHzor Bruker Avance III 400 MHz) operating at 400 MHz using the statedsolvent at around room temperature unless otherwise stated.

In all cases, NMR data were consistent with the proposed structures.Chemical shift are reported as δ values in ppm relative to trimethylsilane (TMS) as an internal standard. Coupling constants (J values) aregiven in hertz (Hz) and multiplicities are reported using the followingabbreviation (s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet,br=broad, nd=not determined).

LC/UV/MS Analytical Methods

LC/MS retention times are estimated to be affected by an experimentalerror of ±0.5 min.

Methods 1-2-3-4:

LC-UV-MS instrument (Waters Acquity UPLC system) equipped with UV (PDAdetector) and mass spectrometer (Acquity QDa Detector). UV acquisitionrange 210-400 nm. MS acquisition range 110-1200 amu.

LC-UV

Eluent A: water/ACN 95/5 (0.05% HCOOH), Eluent B: ACN/water 95/5 (0.05%HCOOH)

Flow 1 mL/min

Column Temperature: 40° C.

Gradient 1:

Time (min) % A % B 0.00 99 1 1.50 0.1 99.9 1.90 0.1 99.9 2.00 99 1

Gradient 2:

Time (min) % A % B 0.00 99 1 3.50 0.1 99.9 3.90 0.1 99.9 4.00 99 1

Methods:

Method Gradient Column 1 Gradient 1 Acquity UPLC BEH C18 1.7 um 50 × 2.1mm 2 Gradient 1 Acquity UPLC CSH C18 1.7 um 50 × 2.1 mm 3 Gradient 2Kinetex UPLC C8 1.7 um 50 × 2.1 mm 4 Gradient 2 Acquity UPLC CSH C18 1.7um 50 × 2.1 mm

MS instrument: Waters ZQ (or equivalent)

Polarity ES

Capillary (kV) 3.20

Cone (V) 25.00

Extractor (V) 3.00

RF Lens (V) 0.1

Polarity ES−

Capillary (kV) 3.40

Cone (V) 24.00

Extractor (V) 2.00

RF Lens (V) 0.2

Source Temperature (° C.) 130

Desolvation Temperature (° C.) 400

Cone Gas Flow (L/Hr) 80

Desolvation Gas Flow (L/Hr) 800

Mass range: 60 to 1200

Scan time (sec): 0.4

Method 5

LC-UV-MS instrument (Waters Acquity UPLC system) equipped with UV (PDAdetector) and mass spectrometer (Waters TQS Detector). UV acquisitionrange 210-400 nm. MS acquisition range 100-1000 amu ESI+ and ESI−

Solvents:

A % HCOONH4 buffer 0.025M pH 3

B % ACN+0.1% HCOOH

Flow (ml/min) 0.5 mL/min

Stop time (mins) 10 min

Column Temperature 55° C.

UV acquisition range (nm): 254

Injection volume (μl): 2

Column: Kinetex 1.7 u C8 100 A 100×2.1 mm

Gradient:

Time (min) % A % B 0.00 99 1 0.5 99 1 3 70 30 6.5 50 50 7.5 20 80 8 2080 8.1 99 1 10 99 1

Method 6

10 cm_Formic_ACE 3 C18 AR_HPLC_CH3CN

HPLC Setup

Solvents:—Acetonitrile (Far UV grade) with 0.1% (V/V) formic acid

-   -   Water (High purity via PureLab Ultra unit) with 0.1% formic acid

Column:—Hichrom ACE 3 C18-AR mixed mode column 100×4.6 mm

Flow Rate:—1 ml/min

Gradient:

Time (min) % A % B 0.00 98 2 3 98 2 12 0 100 15.4 0 100 15.5 98 2 17 982

Injections 0.2-10 ul

Maximum pressure setting 400 bar.

Instrument: Agilent 1100, Binary Pump, Agilent Sampler and Agilent DADdetector

Diode array detection: (300 nm, Band Width 200 nm; Ref. 450 nm, BandWidth 100 nm)

Method 7

15 cm_Formic_Ascentic_HPLC_CH3CN

HPLC Setup

Solvents:—Acetonitrile (Far UV grade) with 0.1% (V/V) formic acid

-   -   Water (High purity via PureLab Ultra unit) with 0.1% formic acid

Column:—Supelco, Ascentis® Express C18 or Hichrom Halo C18, 2.7 μm C18,150×4.6 mm.

Flow Rate:—1 ml/min

Gradient:

Time (min) % A % B 0.00 96 4 3 96 4 9 0 100 13.6 0 100 13.7 96 4 15 96 4

Injections 0.2-10 ul

Maximum pressure setting 400 bar.

Instrument: Agilent 1100, Binary Pump, Agilent Sampler and Agilent DADdetector

Diode array detection: (300 nm, Band Width 200 nm; Ref. 450 nm, BandWidth 100 nm)

Method 8

10 cm_ESCI_Formic_MeCN

HPLC Setup

Solvents:—Acetonitrile (Far UV grade) with 0.1% (V/V) formic acid

-   -   Water (High purity via PureLab Option unit) with 0.1% formic        acid

Column:—Phenomenex Luna 5 u C18 (2), 100×4.6 mm. (Plus guard cartridge)

Flow Rate:—2 ml/min

Gradient:

Time (min) % A % B 0.00 95 5 3.5 5 95 5.5 5 95 5.6 95 5 6.5 95 5

Injections 2-7 ul (concentration ˜0.2-1 mg/ml).

UV detection via HP or Waters DAD

Start Range (nm) 210 End Range (nm) 400 Range interval (nm) 4.0

Other wavelength traces are extracted from the DAD data.

Optional ELS detection using Polymer Labs ELS-1000.

MS detection: Micromass ZQ, single quadrupole LC-MS or Quattro MicroLC-MS-MS.

Flow splitter gives approximately 300 ul/min to mass spec

Scan range for MS Data (m/z)

Start (m/z) 100

End (m/z) 650 or 1500 when required

With +ve/−ve switching

Ionization is routinely ESCI an option which gives both ESI and APCIdata from a single run.

Typical ESI voltages and temperatures are:

Source 120-150C 3.5 KV capillary 25 V cone

Typical APCI voltages and temperatures are:

Source 140-160C 17 uA corona 25 V cone

Method 9. HPLC-AB

-   -   HPLC with UV-Vis or DAD detector    -   column: Waters Symmetry C18, 3.9×150 mm, 5.0 μm

Eluents:

-   -   (A) 0.1% formic acid-water solution    -   (B) 0.1% formic acid-ACN solution    -   injection volume: 3 μL    -   flow: 1.0 ml/min

Gradient:

Time (min) % A % B 0.00 95 5 3 95 5 9 83 17 15 83 17 25 20 80 27 20 8028 95 5 30 95 5

Column compartment:

-   -   column temperature: 25° C.    -   time of analysis: 30 min

Detector:—wave length: 220 nm

Method 10. Chiral-HPLC

Equipment:

-   -   HPLC with UV-Vis or DAD detector    -   column: Chiralpak IC, 4.6 mm×250 mm×5 um

Eluents:

-   -   (A)IPA+0.1% TFA    -   (B)Hexane+0.1% TFA

Autosampler:

-   -   injectionvolume:3 μL

Pump:

-   -   flow: 1.0 ml/min    -   90% B

Column compartment:

-   -   column oven temperature: 25° C.    -   time of analysis: 30 min

Detector:

-   -   wave length: 220 nm

Method 11

10 cm_Formic_AQ

UPLC Setup

Solvents:—B Acetonitrile (Far UV grade) with 0.1% (V/V) formic acid

-   -   A Water (High purity via PureLab Option unit) with 0.1% formic        acid

Column:—Acquity UPLC HSS C18 1.8 um 100×2.1 mm. (Plus guard cartridge)

Flow Rate:—0.5 ml/min

Gradient:

Time (min) % A % B 0.00 95 5 1.2 95 5 3.5 0 100 4.9 0 100 5 95 5 6 95 5

Injections 0.5-2 ul

UV detection via Waters DAD

Start Range (nm) 210 End Range (nm) 400 Resolution (nm) 1.2

MS detection: Waters SQD2, single quadrapole UPLC-MS

Scan range for MS Data (m/z)

Start (m/z) 100

End (m/z) 700 or 1500 when required

With +ve/−ve switching

Ionization is ESI.

ESI voltages and temperatures are:

Source 150 C 3.5 KV capillary 25 V cone

Method 12

10 cm_Bicarb_AQ

UPLC Setup

Solvents:—Acetonitrile (Far UV grade)

Water (High purity via PureLab Option unit) with 10 mM ammoniumbicarbonate (ammonium hydrogen carbonate)

Column:—Acquity UPLC BEH Shield RP18 1.7 um 100×2.1 mm. (Plus guardcartridge)

Flow Rate:—0.5 ml/min

Gradient:—A: Water/Basic B: MeCN/Basic

Time A % B % 0.00 95 5 1.20 95 5 3.5 0 100 4.90 0 100 5.00 95 5 6.00 955

Typical Injections 0.5-2 ul (concentration ˜0.2-1 mg/ml).

UV detection via Waters DAD

Start Range (nm) 210 End Range (nm) 400 Resolution (nm) 1.2

Other wavelength traces are extracted from the DAD data.

MS detection: Waters SQD2, single quadrapole UPLC-MS

Flow splitter gives approximately 300 ul/min to mass spec

Scan range for MS Data (m/z)

Start (m/z) 100

End (m/z) 700 or 1500 when required

With +ve/−ve switching

Preparative Reverse-Phase HPLC Conditions

Preparative HPLC

Waters Micromass ZQ/Sample manager 2767

Photodiode array detector 2996;

Column: XTerra Prep MS C18 Column (5 μm, 19×150 mm, Waters)

Flow rate: 20 ml/min with MS detection

UV wavelength: 254 nm.

Mobile phase: Solvent A (water:MeCN:HCOOH 95:5:0.05); Solvent B(water:MeCN:HCOOH 5:95:0.05)

Gradient:

Time (min) % A % B 0.00 100.0 0.00 1.00 100 0.00 10.00 0.00 100.0 11.000.00 100.0 12.00 100.0 0.00

Where the preparation of starting materials is not described, these arecommercially available, known in the literature, or readily obtainableby those skilled in the art using standard procedures.

Flash chromatography is carried out using an Isolera MPLC system(manufactured by Biotage) using pre-packed silica gel or reverse-phasecartridges (supplied by Biotage).

Many of the compounds described in the following Examples have beenprepared from stereochemically pure starting materials, for example 95%ee.

The stereochemistry of the compounds in the Examples, where indicated,has been assigned on the assumption that absolute configuration atresolved stereogenic centers of staring materials is maintainedthroughout any subsequent reaction conditions.

In the procedures that follow, after each starting material, referenceto a compound number is sometimes provided. This is provided merely forassistance to the skilled chemist. The starting material may notnecessarily have been prepared from the batch referred to.

When reference is made to the use of a “similar” or “analogous”procedure, as will be appreciated by those skilled in the art, such aprocedure may involve minor variations, for example reactiontemperature, reagent/solvent amount, reaction time, work-up conditionsor chromatographic purification conditions.

Preparation of(R)-5-(2-Amino-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one hydrochloride

Step 1; 8-(Benzyloxy)-5-(2-bromoacetyl)quinolin-2(1H)-one

A suspension of 5-acetyl-8-(benzyloxy)quinolin-2(1H)-one (19.4 g, 66.4mmol) in anhydrous THF (240 mL) and anhydrous methanol (165 mL) wasadded with a solution of tetra-n-butylammonium tribromide (54.5 g, 113.0mmol) in anhydrous THF (130 mL) drop-wise over 1.5 hours. The resultingsolution was stirred at room temperature overnight before concentratingunder reduced pressure without heating. The residue was re-dissolved inmethanol (200 mL). Saturated aqueous ammonium chloride solution (390 mL)was added with ice-cooling. The resulting suspension was filtered andthe solid washed with water and air-dried under vacuum. The solid wassuspended in DCM and methanol (1:1 v/v, 100 mL) for 90 minutes. Thesolid was collected by filtration, washed with DCM and air-dried toafford the title compound (18.0 g, 73%).

¹H NMR (400 MHz, DMSO-d₆): δ 11.07 (s, 1H), 8.51 (d, J=10.0 Hz, 1H),7.94-7.83 (m, 1H), 7.60 (d, J=7.5 Hz, 2H), 7.44-7.27 (m, 4H), 6.79-6.65(m, 1H), 5.53-5.39 (s, 2H), 4.93 (s, 2H)

Step 2; (R)-8-(Benzyloxy)-5-(2-bromo-1-hydroxyethyl)quinolin-2(1H)-one

8-(Benzyloxy)-5-(2-bromoacetyl)quinolin-2(1H)-one (26.0 g, 69.9 mmol)and(R)-3,3-diphenyl-1-methyltetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazaborole(21.3 g, 76.8 mmol) were azeotroped with toluene (×3) then suspended inanhydrous THF (400 mL) under an atmosphere of nitrogen. The suspensionwas cooled to −20° C. (external temperature) and borane dimethyl sulfidecomplex solution (45.4 mL, 90.8 mmol, 2.0M solution in THF) was added bysyringe pump over 3 hours, After complete addition the reaction mixturewas stirred for one hour before quenching with methanol (25 mL). Thereaction was warmed to room temperature over 20 minutes. The mixture wasconcentrated under reduced pressure and the residue was suspended inaqueous hydrochloric acid (500 mL, 1M solution) and stirred at roomtemperature for 18 hours.

After this time the solid was collected by filtration and washed withwater (3×100 mL). The solid was partially dissolved in ethyl acetate andheated at reflux for 2 hours. The remaining solid was removed by hotfiltration and the filtrate was evaporated to afford the title compound.The solid collected from the hot ethyl acetate was again partiallydissolved in ethyl acetate and heated at reflux for 2 hours thenfiltered to give filtrate containing pure product. This process wasrepeated four more times. The combined solid was recrystallised fromethyl acetate and petroleum ether to afford the title compound (20.0 g,76%).

¹H NMR (400 MHz, DMSO-d₆): δ 10.68 (s, 1H), 8.19 (d, J=9.9 Hz, 1H), 7.58(d, J=7.5 Hz, 2H), 7.41-7.36 (m, 2H), 7.34-7.29 (m, 1H), 7.23-7.19 (m,2H), 6.57 (d, J=9.8 Hz, 1H), 5.94 (d, J=4.7 Hz, 1H), 5.31 (s, 2H);5.25-5.19 (m, 1H), 3.71-3.58 (m, 2H).

Step 3;(R)-8-(Benzyloxy)-5-(2-bromo-1-((tert-butyldimethylsilyl)oxy)ethyl)quinolin-2(1H)-one

2,6-Lutidine (6.9 mL, 59.5 mmol) was added to a solution of(R)-8-(benzyloxy)-5-(2-bromo-1-hydroxyethyl)quinolin-2(1H)-one (10.1 g,27.0 mmol) in DCM (100 mL) at 0° C. The reaction mixture was stirred for5 minutes then tert-butyldimethylsilyl trifluoromethanesulfonate (13.0mL, 56.8 mmol) was added dropwise over 15 minutes. The mixture wasstirred at 0° C. for 30 minutes, followed by room temperature overnight.After this time the reaction was quenched with saturated aqueous sodiumbicarbonate solution and extracted with DCM (×3). The combined organicextracts were dried (magnesium sulfate), filtered and concentrated underreduced pressure. Iso-hexane (500 mL) was added to the crude materialand the resulting solid collected by filtration. The solid wasrecrystallised from ethyl acetate and petroleum ether (40:60) to affordthe title compound (11.3 g, 85%).

¹H NMR (400 MHz, CDCl₃): δ 9.19 (s, 1H), 8.23 (dd, J=9.9, 4.4 Hz, 1H),7.43 (d, J=4.6 Hz, 5H), 7.17 (dd, J=8.3, 4.5 Hz, 1H), 7.03 (dd, J=8.2,4.4 Hz, 1H), 6.71 (dd, J=9.9, 3.7 Hz, 1H), 5.18 (d, J=4.5 Hz, 3H),3.63-3.56 (m, 1H), 3.49 (dd, J=10.4, 4.8 Hz, 1H), 0.88 (t, J=4.4 Hz,9H), 0.14 (d, J=4.4 Hz, 3H), −0.11 (d, J=4.4 Hz, 3H).

Step 4;(R)-5-(2-Azido-1-((tert-butyldimethylsilyl)oxy)ethyl)-8-(benzyloxy)quinolin-2(1H)-one

(R)-8-(Benzyloxy)-5-(2-bromo-1-((tert-butyldimethylsilyl)oxy)ethyl)-quinolin-2(1H)-one(10.0 g, 20.5 mmol) was dissolved in DMF (180 mL) and water (20 mL).Sodium iodide (3.39 g, 22.6 mmol) and sodium azide (1.47 g, 22.6 mmol)were added sequentially. The reaction mixture was stirred at RT untilall the solid was in solution. The solution was heated at 80° C. for 40hours then cooled to RT and diluted with ethyl acetate (300 mL). Themixture was washed with water, brine (×2) and the organic extract wasdried (magnesium sulfate), filtered and concentrated under reducedpressure. The crude residue was triturated with iso-hexane to afford thedesired compound (8.16 g, 88%). Used without further purification in thenext step.

¹H NMR (400 MHz, CDCl₃): δ 9.19 (s, 1H), 8.18 (d, J=9.9 Hz, 1H),7.45-7.36 (m, 5H), 7.20 (d, J=8.3 Hz, 1H), 7.04 (d, J=8.3 Hz, 1H), 6.70(dd, J=9.9, 2.2 Hz, 1H), 5.19-5.13 (m, 3H), 3.48 (dd, J=12.7, 8.1 Hz,1H), 3.26 (dd, J=12.7, 3.8 Hz, 1H), 0.89 (s, 9H), 0.14 (s, 3H), −0.11(s, 3H).

Step 5; (R)-5-(2-Amino-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-onehydrochloride

A solution of(R)-5-(2-azido-1-((tert-butyldimethylsilyl)oxy)ethyl)-8-(benzyloxy)quinolin-2(1H)-one(4.50 g, 10.0 mmol) in ethanol (50 mL) was added with 10% palladium oncharcoal (4.50 g) followed by 1-methyl-1,4-cyclohexadiene (11.0 mL, 97.9mmol). The reaction was warmed to 60° C. and then stirred at 60° C. for2 hours. The reaction mixture was allowed to cool and filtered through apad of celite. The filtercake was washed with further ethanol and thefiltrate was evaporated under reduced pressure. The residue wasevaporated from iso-propanol (×2) and dissolved in iso-propanol (30 mL).HCl-dioxane (4M, 50 mL, 200 mmol) was added and the reaction mixturestirred at room temperature for 18 hours. The resulting suspension wasfiltered, the filtercake washed with ether and the solid dried undervacuum in the presence of P₂O₅ to afford the title compound (1.65 g,62%).

¹H NMR (400 MHz, MeOD): δ 7.71 (d, J=9.8 Hz, 1H), 6.57 (d, J=8.2 Hz,1H), 6.31 (d, J=8.2 Hz, 1H), 6.02 (dd, J=9.8, 6.5 Hz, 1H), 4.58 (dd,J=9.6, 3.5 Hz, 1H), 2.47-2.31 (m, 2H).

Example 1. (1-Benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-((5-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)pentyl)oxy)phenyl)-2-phenylacetate(Compound 1)

Step 1; Ethyl 2-(3-(benzyloxy)phenyl)-2-hydroxy-2-phenylacetate

A stirred solution of ethyl benzoylformate (1.78 g, 10.0 mmol) in THF(30 mL) at −78° C. was added drop-wise with a solution of3-benzyloxyphenyl magnesium bromide (1.0M solution in THF, 11.0 mL, 11.0mmol) over 20 minutes. The reaction mixture was allowed to warm slowlyto room temperature and stirred at room temperature for 18 hours. Thereaction mixture was quenched with 10% aqueous HCl and then extractedwith ethyl acetate. The ethyl acetate extract was washed with brine,dried over anhydrous magnesium sulfate and the filtrate was evaporatedunder reduced pressure. The residue was purified by flash columnchromatography (eluent—100% iso-hexane to 12:1 iso-hexane/ethyl acetate)to afford the title compound (2.23 g, 62%).

¹H NMR (400 MHz, CDCl₃); δ 7.44-7.23 (m, 11H), 7.13-7.09 (m, 1H),7.05-7.04 (m, 1H), 6.95-6.92 (m, 1H), 5.04 (s, 2H), 4.34-4.32 (m, 2H),4.23 (s, 1H), 1.28-1.25 (m, 3H).

Step 2; Ethyl 2-hydroxy-2-(3-hydroxyphenyl)-2-phenylacetate

10% Pd—C (2.0 g) was added to a solution of ethyl2-(3-(benzyloxy)phenyl)-2-hydroxy-2-phenylacetate (2.22 g, 6.13 mmol) inethanol (20 mL). After 5 minutes 1-methyl-1,4-cyclohexadiene (3.5 mL,31.1 mmol) was added and the reaction mixture carefully heated to 70° C.[CARE—Vigorous evolution of gas]. The reaction mixture was heated atthis temperature for 30 minutes and the reaction mixture was allowed tocool. The suspension was filtered and the filter-cake washed withfurther ethanol. The filtrate was evaporated under reduced pressure. Theresidue was purified by flash column chromatography (eluent—100%iso-hexane to 4:1 iso-hexane/ethyl acetate) to afford the title compound(1.20 g, 72%).

¹H NMR (400 MHz, CDCl₃); δ 7.44-7.42 (m, 2H), 7.36-7.29 (m, 3H),7.22-7.19 (m, 1H), 7.02-6.99 (m, 1H), 6.93-6.92 (m, 1H), 6.80-6.78 (m,1H), 4.81 (s, 1H), 4.35-4.27 (m, 2H), 4.23 (s, 1H), 1.30-1.26 (m, 3H).

Step 3; Ethyl2-(3-(4-(1,3-dioxolan-2-yl)butoxy)phenyl)-2-hydroxy-2-phenylacetate

A stirred solution of ethyl2-hydroxy-2-(3-hydroxyphenyl)-2-phenylacetate (1.19 g, 4.38 mmol) in DMF(15 mL) was added with potassium carbonate (0.907 g, 6.57 mmol). Thereaction mixture was stirred at room temperature for 10 minutes and then2-(4-chlorobutyl)-1,3-dioxolane (0.78 mL, 5.25 mmol) was added. Thereaction mixture was heated at 80° C. for 42 hours. 10% Aqueouspotassium hydrogen sulfate was added to the reaction mixture which wasthen extracted with ethyl acetate. The organic phase was washed withbrine, dried over anhydrous magnesium sulfate and the filtrate wasevaporated under reduced pressure. The residue was purified by flashcolumn chromatography (eluent—100% iso-hexane to 4:1 iso-hexane/ethylacetate) to afford the title compound (1.07 g, 61%).

¹H NMR (400 MHz, CDCl₃); δ 7.44-7.42 (m, 2H), 7.34-7.31 (m, 3H),7.25-7.21 (m, 1H), 7.02-6.98 (m, 2H), 6.85-6.82 (m, 1H), 4.88-4.86 (m,1H), 4.35-4.30 (m, 2H), 4.22 (s, 1H), 3.97-3.83 (m, 6H), 1.83-1.71 (m,4H), 1.61-1.59 (m, 2H), 1.28-1.22 (m, 3H).

Step 4;2-(3-(4-(1,3-Dioxolan-2-yl)butoxy)phenyl)-2-hydroxy-2-phenylacetic acid

A stirred solution of ethyl2-(3-(4-(1,3-dioxolan-2-yl)butoxy)phenyl)-2-hydroxy-2-phenylacetate(1.06 g, 2.65 mmol) in ethanol (10 mL) was added with 2M aqueous sodiumhydroxide (10 mL). The reaction mixture was stirred at room temperaturefor 72 hours. The reaction mixture was treated with 10% aqueouspotassium hydrogen sulfate and extracted with DCM (×2) and ethylacetate. The combined organic phases were dried over anhydrous magnesiumsulfate and the filtrate was evaporated under reduced pressure to affordthe title compound (1.09 g, >100%).

¹H NMR (400 MHz, CDCl₃); δ 7.44-7.42 (m, 2H), 7.34-7.31 (m, 3H),7.25-7.21 (m, 1H), 7.02-6.98 (m, 2H), 6.85-6.82 (m, 1H), 4.88-4.86 (m,1H), 4.10-3.83 (m, 6H), 1.83-1.71 (m, 4H), 1.61-1.55 (m, 2H).

Step 5; tert-Butyl 4-(tosyloxymethyl)piperidine-1-carboxylate

A stirred solution of tert-butyl4-(hydroxymethyl)piperidine-1-carboxylate (5.0 g, 23.2 mmol) inanhydrous pyridine (18.5 mL) at 0° C. under nitrogen was added withp-toluenesulfonyl chloride (4.87 g, 25.55 mmol) in one portion. Thereaction was stirred at 0° C. for 100 minutes before warming to roomtemperature. After 18 hours the reaction mixture was poured into waterand extracted with ethyl acetate (×3). The combined organic extractswere washed with aqueous 1M hydrochloric acid (×2), brine, dried(magnesium sulfate), filtered and evaporated under reduced pressure toyield the title compound as a yellow solid (7.87 g, 91%).

¹H NMR (400 MHz, CDCl₃): δ 7.78 (d, J=8.4 Hz, 2H), 7.35 (d, J=8.0 Hz,2H), 4.15-4.07 (m, 2H), 3.85 (d, J=6.5 Hz, 2H), 2.68-2.60 (m, 2H), 2.46(s, 3H), 1.88-1.78 (m, 1H), 1.66-1.59 (m, 2H), 1.44 (s, 9H), 1.16-1.04(m, 2H).

Step 6; tert-Butyl4-((2-(3-(4-(1,3-dioxolan-2-yl)butoxy)phenyl)-2-hydroxy-2-phenylacetoxy)methyl)piperidine-1-carboxylate

A stirred solution of2-(3-(4-(1,3-dioxolan-2-yl)butoxy)phenyl)-2-hydroxy-2-phenylacetic acid(1.0 g, 2.69 mmol) in DMF (10 mL) was added with potassium carbonate(0.558 g, 4.04 mmol). After 10 minutes tert-butyl4-(tosyloxymethyl)piperidine-1-carboxylate (1.29 g, 3.50 mmol) was addedand the resulting mixture heated at 80° C. for 18 hours. The reactionmixture was diluted with ethyl acetate and washed with water and brine(twice). The organic phase was dried over anhydrous magnesium sulfateand the filtrate was evaporated under reduced pressure. The residue waspurified by flash column chromatography (eluent—100% iso-hexane to 4:1iso-hexane/ethyl acetate) to afford the title compound (1.42 g, 93%).

¹H NMR (400 MHz, CDCl₃); δ 7.44-7.42 (m, 2H), 7.34-7.31 (m, 3H),7.25-7.21 (m, 1H), 7.02-6.98 (m, 2H), 6.85-6.82 (m, 1H), 4.88-4.86 (m,1H), 4.19-3.83 (m, 11H), 2.60 (m, 2H), 1.88-1.71 (m, 4H), 1.61-1.58 (m,3H), 1.54-1.46 (m, 11H), 1.26-1.24 (m, 2H).

Step 7; Piperidin-4-ylmethyl2-(3-(4-(1,3-dioxolan-2-yl)butoxy)phenyl)-2-hydroxy-2-phenylacetatehydrochloride

A solution of HCl in dioxane (4M, 10 mL) was added to tert-butyl4-((2-(3-(4-(1,3-dioxolan-2-yl)butoxy)phenyl)-2-hydroxy-2-phenylacetoxy)methyl)piperidine-1-carboxylate(1.40 g, 2.46 mmol) and the mixture stirred at room temperature for 2hours.

The solvent was evaporated under reduced pressure and the residue useddirectly in the next step with no purification.

Step 8; (1-Benzylpiperidin-4-yl)methyl2-(3-(4-(1,3-dioxolan-2-yl)butoxy)phenyl)-2-hydroxy-2-phenylacetate

A stirred solution of piperidin-4-ylmethyl2-(3-(4-(1,3-dioxolan-2-yl)butoxy)phenyl)-2-hydroxy-2-phenylacetatehydrochloride in acetonitrile (15 mL) was added with triethylamine(0.683 mL, 4.91 mmol). The reaction mixture was stirred at roomtemperature for 20 minutes. Benzaldehyde (0.325 mL, 3.20 mmol) was addedand the mixture stirred for a further 30 minutes. To this mixture wasadded sodium triacetoxyborohydride (1.04 g, 4.91 mmol) followed byacetic acid (0.562 mL, 9.82 mmol). The resulting mixture was stirred atroom temperature for 72 hours. The reaction mixture was diluted withethyl acetate and washed with 10% aqueous potassium carbonate and brine.The organic phase was dried and the filtrate was evaporated underreduced pressure. The residue was purified by flash columnchromatography (eluent—100% DCM to 25:1 DCM/methanol) to afford thetitle compound (0.804 g, 58%).

¹H NMR (400 MHz, CDCl₃); δ 7.42-7.38 (m, 2H), 7.35-7.19 (m, 9H),7.00-6.94 (m, 2H), 6.83 (ddd, J=8.2, 2.5, 0.9 Hz, 1H), 5.30 (s, 2H),4.88-4.83 (m, 1H), 4.22 (s, 1H), 4.15-4.06 (m, 2H), 4.01-3.80 (m, 6H),3.45 (s, 2H), 2.81 (d, J=11.3 Hz, 2H), 1.92-1.66 (m, 6H), 1.70-1.46 (m,3H), 1.28-1.13 (m, 2H).

Step 9; (Compound 1)

To a stirred solution of (1-benzylpiperidin-4-yl)methyl2-(3-(4-(1,3-dioxolan-2-yl)butoxy)phenyl)-2-hydroxy-2-phenylacetate(0.390 g, 0.70 mmol) in THF (4 mL) was added 10% aqueous hydrochloricacid (8 mL), The resulting mixture was stirred at room temperature for 2hours. To the mixture was added 10% aqueous potassium carbonate and thenextracted with ethyl acetate (twice). The combined organic phases weredried and the filtrate was evaporated under reduced pressure. Theresidue was dissolved in methanol (3 mL) and added to a pre-stirred (10minutes) mixture of(R)-5-(2-amino-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one hydrochloride(0.193 g, 0.60 mmol, 80% purity) and triethylamine (0.167 mL, 1.20 mmol)in methanol (3 mL). This mixture was stirred at room temperature for 1hour and then sodium triacetoxyborohydride (0.254 g, 1.20 mmol) followedby acetic acid (0.137 mL, 2.39 mmol) were added. The reaction mixturewas stirred for a further 1 hour. The reaction mixture was diluted withiso-butanol and washed with water. The aqueous phase was extracted withfurther iso-butanol. The combined iso-butanol extracts were evaporatedunder reduced pressure. The residue was purified by reverse phasepreparative HPLC to afford the title compound (1).

The following compounds were prepared as described in Example 1 with thecorresponding commercially available substituted ethyl benzoylformatereplacing ethyl benzoylformate in Step 1. If the required substitutedethyl benzoylformate was not available it was prepared according toScheme 2 and Procedure 1 using the appropriate Grignard reagent.

Salt (2 eq R_(t) Meth- unless (min) Structure od NMR data (400 MHz)stated) 1 8.46

6 (DMSO-d₆/D₂O); δ 8.19 (d, J = 9.9 Hz, 1 H); 7.45 (s, 5 H); 7.30 (d, J= 7.6 Hz, 6 H); 7.22 (d, J = 8.1 Hz, 1 H); 7.16 (d, J = 8.2 Hz, 1H);7.00 (d, J = 8.2 Hz, 1 H); 6.86-6.79 (m, 3 H); 6.60 (d, J = 9.8 Hz, 1H); 5.31-5.24 (m, 1 H); 4.20 (s, 3 H); 4.05-3.71 (m, 4 H); 3.32-3.24 (m,2 H); 3.07 (s, 2 H); 2.96 (s, 2 H); 2.87 (s, 2 H); 1.85 (s, 1 H);1.76-1.61 (m, 5 H); 1.45-1.27 (m, 3 H) TFA 2 7.29

7 (DMSO-d₆); δ 8.31 (s, 2H), 8.19 (d, J = 9.9 Hz, 1 H), 7.32-7.18 (m,9H), 7.14- 7.09 (m, 3H), 6.96 (d, J = 8.2 Hz, 1H), 6.88-6.83 (m, 3H),6.53 (d, J = 9.9 Hz, 1H), 5.20 (dd, J = 4.5, 8.2 Hz, 1H), 4.01-3.96 (m,2H), 3.89 (dd, J = 6.3, 6.3 Hz, 2H), 3.40 (s, 2H), 2.89-2.69 (m, 6H),2.28 (s, 3H), 1.83 (dd, J = 9.5, 11.8 Hz, 2H), 1.72-1.63 (m, 2H), 1.60-1.37 (m, 7H), 1.17-1.04 (m, 2H). Formate 3 7.23

7 (DMSO-d₆); δ 10.54-10.49 (m, 2H), 8.60-8.59 (m, 2H), 7.48 (s, 5H),7.38- 7.33 (m, 2H), 7.25 (dd, J = 8.0, 8.0 Hz, 1H), 7.18-7.13 (m, 3H),6.99 (d, J = 8.2 Hz, 1H), 6.90-6.85 (m, 3H), 6.58 (d, J = 9.9 Hz, 1H),6.33-6.01 (s, 1H), 5.32 (dd, J = 2.2, 9.6 Hz, 1H), 4.31-4.20 (m, 2H),4.01 (d, J = 6.4 Hz, 2H), 3.91 (dd, J = 6.3, 6.3 Hz, 2H), 3.34 (d, J =14.1 Hz, 2H), 3.12-2.86 (m, 6H), 1.85-1.83 (m, 1H), 1.77 (s, 1H),1.72-1.64 (m, 6H), 1.48-1.30 (m, 4H). TFA 4 7.23

7 (DMSO-d₆); δ 10.52 (s, 2H), 9.49-9.49 (m, 1H), 8.60-8.59 (m, 2H), 8.16(d, J = 9.9 Hz, 1H), 7.48 (s, 6H), 7.42-7.35 (m, 1H), 7.26 (dd, J = 7.9,7.9 Hz, 1H), 7.19-7.10 (m, 4H), 6.99 (d, J = 8.2 Hz, 1H), 6.91-6.86 (m,4H), 6.58 (d, J = 9.9 Hz, 1H), 6.14-6.14 (m, 1H), 5.30 (dd, J = 2.2, 9.7Hz, 1H), 4.31-4.21 (m, 3H), 4.02 (d, J = 6.5 Hz, 2H), 3.91 (dd, J = 6.2,6.2 Hz, 2H), 3.34 (d, J = 11.8 Hz, 2H), 3.10-2.86 (m, 5H), 1.89-1.84 (m,1H), 1.77-1.64 (m, 5H), 1.48-1.30 (m, 4H). TFA 5 7.28

7 (DMSO-d₆); δ 10.52-10.46 (2H, m), 9.49-9.36 (1H, m), 8.57-8.56 (2H,m), 8.16 (1H, d, J = 7.3 Hz), 7.48 (5H, s), 7.26-7.19 (2H, m), 7.15 (2H,d, J = 8.2 Hz), 7.09 (2H, dd, J = 8.3, 8.3 Hz), 6.99 (1H, d, J = 8.2Hz), 6.89-6.83 (3H, m), 6.58 (2H, dd, J = 1.9, 9.9 Hz), 6.17- 6.16 (1H,m), 5.31 (1H, d, J = 8.9 Hz), 4.26 (2H, d, J = 4.9 Hz), 4.01 (2H, d, J =6.4 Hz), 3.91 (2H, dd, J = 6.3, 6.3 Hz), 3.34 (2H, d, J = 11.5 Hz),3.11- 2.86 (6H, m), 2.27 (3H, s), 1.84 (1H, d, J = 3.1 Hz), 1.76-1.64(6H, m), 1.48-1.34 (4H, m); TFA 6 8.12

7 (MeOD); δ 8.38 (d, J = 9.7 Hz, 1H), 7.54-7.47 (m, 5H), 7.44 (d, J =7.8 Hz, 1H), 7.35-7.28 (m, 3H), 7.27 (s, 1H), 7.19-7.10 (m, 2H), 7.05(d, J = 8.2 Hz, 1H), 6.98-6.91 (m, 2H), 6.70 (d, J = 9.9 Hz, 1H), 5.41(t, J = 6.9 Hz, 1H), 4.29 (s, 2H), 4.12-4.02 (m, 4H), 3.50-3.44 (m, 2H),3.25 (d, J = 6.4 Hz, 2H), 3.12 (t, J = 9.1 Hz, 2H), 2.97 (t, J = 12.2Hz, 2H), 2.06-2.00 (m, 1H), 1.93-1.82 (m, 6H), 1.63 (t, J = 17.3 Hz,2H), 1.57- 1.42 (m, 2H). TFA 7 8.15

7 (MeOD); δ 8.38 (d, J = 9.7 Hz, 1H), 7.53-7.48 (m, 5H), 7.32-7.19 (m,4H), 7.13 (s, 1H), 7.07-6.99 (m, 3H), 6.93- 6.86 (m, 2H), 6.70 (d, J =9.8 Hz, 1H), 5.43-5.38 (m, 1H), 4.28 (s, 2H), 4.10 (d, J = 6.5 Hz, 2H),4.01 (dd, J = 6.1, 6.1 Hz, 2H), 3.51-3.45 (m, 2H), 3.25 (d, J = 6.5 Hz,2H), 3.15-3.09 (m, 2H), 2.97 (dd, J = 10.8, 13.1 Hz, 2H), 2.29- 2.21 (m,4H), 2.01-1.96 (m, 1H), 1.89- 1.80 (m, 5H), 1.66-1.58 (m, 2H), 1.50-1.36 (m, 2H). TFA 8 7.36

7 (MeOD); δ 8.38 (d, J = 9.9 Hz, 1H), 7.51-7.48 (m, 5H), 7.33-7.23 (m,4H), 7.10 (s, 1H), 7.07-7.03 (m, 2H), 6.99 (d, J = 7.8 Hz, 1H),6.92-6.84 (m, 2H), 6.70 (d, J = 9.9 Hz, 1H), 5.41 (t, J = 8.5 Hz, 1H),4.38-4.24 (m, 2H), 4.09 (d, J = 6.5 Hz, 2H), 4.00 (t, J = 7.0 Hz, 2H),3.51-3.45 (m, 2H), 3.25 (d, J = 6.4 Hz, 2H), 3.16-3.08 (m, 2H), 2.96 (t,J = 12.7 Hz, 2H), 2.64-2.56 (m, 2H), 2.06-1.95 (m, 1H), 1.86-1.78 (m,6H), 1.65-1.59 (m, 2H), 1.49-1.24 (m, 2H), 1.08 (t, J = 8.2 Hz, 3H). TFA9 7.15

7 (DMSO-d₆); δ 10.49 (d, J = 10.4 Hz, 2H), 9.52-9.52 (m, 1H), 8.59-8.58(m, 2H), 8.17 (d, J = 9.9 Hz, 1H), 7.48 (s, 6H), 7.25 (dd, J = 7.9, 7.9Hz, 1H), 7.15 (d, J = 8.2 Hz, 1H), 7.06-7.02 (m, 2H), 7.00-6.94 (m, 4H),6.86 (dd, J = 2.2, 8.0 Hz, 1H), 6.59 (dd, J = 1.6, 9.9 Hz, 1H),6.17-6.17 (m, 1H), 5.30 (d, J = 9.5 Hz, 1H), 4.26 (d, J = 4.9 Hz, 2H),4.01 (d, J = 6.4 Hz, 2H), 3.91 (dd, J = 6.2, 6.2 Hz, 2H), 3.37-3.32 (m,2H), 3.10-2.86 (m, 6H), 1.90-1.84 (m, 1H), 1.79-1.66 (m, 6H), 1.47-1.33(m, 4H). TFA 10 7.36

7 (DMSO-d₆, 90° C.); δ 8.15 (d, J = 9.9 Hz, 1H), 7.50-7.39 (m, 5H), 7.20(dd, J = 7.8, 7.8 Hz, 1H), 7.12 (dd, J = 8.2, 8.2 Hz, 3H), 6.98 (d, J =8.2 Hz, 1H), 6.80-6.76 (m, 1H), 6.54 (d, J = 9.8 Hz, 1H), 5.31 (dd, J =4.4, 8.3 Hz, 1H), 4.20 (s, 2H), 3.95 (dd, J = 6.3, 6.3 Hz, 4H),3.58-3.19 (m, 5H), 3.15-3.07 (m, 2H), 3.02 (dd, J = 7.7, 7.7 Hz, 2H),2.88 (s, 1H), 2.13 (dd, J = 10.9, 10.9 Hz, 1H), 1.76-1.68 (m, 6H), 1.58(d, J = 9.3 Hz, 2H), 1.52-1.33 (m, 6H), 1.23 (d, J = 13.1 Hz, 1H),1.14-0.98 (m, 4H). TFA 11 7.35

7 (DMSO-d₆); δ 10.52 (s, 1H), 10.48 (s, 1H), 9.43 (s, 1H), 8.57 (s, 2H),8.15 (d, J = 9.9 Hz, 1H), 7.47 (s, 4H), 7.24 (dd, J = 7.4, 7.4 Hz, 2H),7.19-7.13 (m, 3H), 7.10 (d, J = 7.8 Hz, 1H), 6.99 (d, J = 8.2 Hz, 1H),6.91-6.84 (m, 3H), 6.61-6.56 (m, 2H), 6.54 (s, 1H), 6.17 (d, J = 3.3 Hz,1H), 5.30 (d, J = 9.4 Hz, 1H), 4.30- 4.25 (m, 2H), 4.01 (d, J = 5.6 Hz,1H), 3.91 (dd, J = 6.2, 6.2 Hz, 2H), 3.16-2.81 (m, 9H), 2.61-2.53 (m,2H), 1.83 (s, 1H), 1.74-1.64 (m, 6H), 1.47-1.30 (m, 4H), 1.13 (dd, J =7.5, 7.5 Hz, 3H). TFA

Procedure 1 Preparation of ethyl 3-methylbenzoylformate

A stirred solution of diethyl oxalate (5 g, 32.2 mmol) in THF (100 mL)was cooled to −78° C. and then a solution of 3-methylphenyl magnesiumbromide (0.5M in THF, 75 mL, 37.5 mmol) was added drop-wise over 25minutes. The reaction mixture was held at −78° C. for 30 minutes andthen the mixture warmed to room temperature. The reaction mixture wasstirred at room temperature for 3 hours and then cooled to 0° C. 10%Aqueous hydrochloric acid was added followed by ethyl acetate. Themixture was stirred vigorously for 30 minutes and the organic phaseremoved. The aqueous phase was extracted with further ethyl acetate andthe combined organic extracts washed with brine, and dried overanhydrous magnesium sulfate. The filtrate was evaporated under reducedpressure and the residue was purified by flash column chromatography(eluent—100% iso-hexane to 5:1 iso-hexane/ethyl acetate) to afford thetitle compound (3.0 g, 49%).

¹H NMR (400 MHz, CDCl₃); δ 7.81-7.79 (m, 2H), 7.48-7.46 (m, 1H),7.45-7.37 (m, 1H), 4.44 (m, 2H), 2.42 (s, 3H), 1.42 (m, 3H).

Example 2. (R)-Quinuclidin-3-yl2-hydroxy-2-(3-((5-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)pentyl)oxy)phenyl)-2-(4-methoxyphenyl)acetate(Compound 12)

Step 1;2-(3-(4-(1,3-Dioxolan-2-yl)butoxy)phenyl)-2-hydroxy-2-(4-methoxyphenyl)aceticacid

The title compound was prepared as described in Example 1 Steps 1 to 4with ethyl 4-methoxybenzoylformate replacing ethyl benzoylformate inStep 1.

¹H NMR (400 MHz, DMSO-d₆); δ 7.34 (d, J=8.9 Hz, 2H), 7.16 (dd, J=8.2,8.2 Hz, 1H), 6.98 (d, J=7.2 Hz, 2H), 6.82 (d, J=8.8 Hz, 2H), 6.80-6.75(m, 1H), 4.78 (dd, J=4.7, 4.7 Hz, 1H), 3.87-3.72 (m, 9H), 1.75-1.57 (m,4H), 1.51-1.44 (m, 2H).

Step 2; (R)-Quinuclidin-3-yl2-(3-(4-(1,3-dioxolan-2-yl)butoxy)phenyl)-2-hydroxy-2-(4-methoxyphenyl)acetate

A solution of2-(3-(4-(1,3-dioxolan-2-yl)butoxy)phenyl)-2-hydroxy-2-(4-methoxyphenyl)aceticacid (0.200 g, 0.50 mmol) in THF (20 mL) was added withcarbonyldiimidazole (0.105 g, 0.65 mmol) and the reaction mixture heatedunder reflux for 2 hours. The reaction mixture was allowed to cool toroom temperature and (R)-quinuclidinol (0.215 g, 1.69 mmol) added. Thereaction mixture was heated under reflux for 72 hours. The reactionmixture was diluted with ethyl acetate and washed sequentially with 10%aqueous sodium carbonate and brine, and dried over anhydrous magnesiumsulfate. The filtrate was evaporated under reduced pressure and thecrude material used in the next step with no purification.

Step 3; (Compound 12)

The title compound (12) was prepared as described in Example 1 Step 9.

Salt (2 eq N R_(t) (min) Method NMR data (400 MHz) unless stated) 126.96 7 (MeOD); δ 8.53 (s, 2H), 8.38 (d, J = 9.9 Hz, 1H), 7.35-7.25 (m,4H), Formate 7.06-6.99 (m, 3H), 6.97-6.89 (m, 3H), 6.72-6.68 (m, 1H),5.40 (t, J = 9.7 Hz, 1H), 5.13-5.11 (m, 1H), 4.02-3.96 (m, 2H), 3.81 (s,3H), 3.52-3.45 (m, 1H), 3.23 (d, J = 6.4 Hz, 2H), 3.10 (t, J = 9.7 Hz,2H), 3.06-2.99 (m, 3H), 2.88-2.73 (m, 2H), 2.19 (d, J = 1.6 Hz, 1H),1.90-1.77 (m, 6H), 1.65-1.52 (m, 4H).

Example 3. (R)-Quinuclidin-3-yl2-cyclopentyl-2-hydroxy-2-(3-((5-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)pentyl)oxy)-phenyl)acetate(Compound 12A)

Step 1; Ethyl 2-(3-(benzyloxy)phenyl)-2-oxoacetate

The title compound was prepared as described in Procedure 1.

¹H NMR (400 MHz, DMSO-d₆); δ 7.57-7.52 (m, 3H), 7.49-7.39 (m, 5H),7.37-7.32 (m, 1H), 5.21 (s, 2H), 4.42 (q, J=7.1 Hz, 2H), 1.33 (dd,J=7.2, 7.2 Hz, 3H).

Step 2;2-(3-(4-(1,3-Dioxolan-2-yl)butoxy)phenyl)-2-cyclopentyl-2-hydroxyaceticacid

The title compound was prepared as described in Example 1 Steps 1 to 4with ethyl 2-(3-(benzyloxy)phenyl)-2-oxoacetate and cyclopentylmagnesium bromide replacing ethyl benzoylformate and 3-benzyloxyphenylmagnesium bromide respectively in Step 1.

¹H NMR (400 MHz, DMSO-d6); δ 7.34 (d, J=8.9 Hz, 2H), 7.16 (dd, J=8.2,8.2 Hz, 1H), 6.98 (d, J=7.2 Hz, 2H), 6.82 (d, J=8.8 Hz, 2H), 6.80-6.75(m, 1H), 4.78 (dd, J=4.7, 4.7 Hz, 1H), 3.87-3.72 (m, 9H), 1.75-1.57 (m,4H), 1.51-1.44 (m, 2H).

Step 3; (R)-Quinuclidin-3-yl2-cyclopentyl-2-hydroxy-2-(3-((5-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)pentyl)oxy)phenyl)acetate(Compound 12A)

The title compound was prepared as described in Example 2 Step 2 and 3to afford the title compound (12A).

Salt (2 eq N Rt (min) Method NMR data (400 MHz) unless stated) 12A 7.056 (MeOD) δ 8.39 (d, J = 9.9 Hz, 1H), 7.32-7.21 (m, 4H), 7.05 (d, J = 8.2Hz, TFA 1H), 6.88-6.84 (m, 1H), 6.70 (d, J = 9.9 Hz, 1H), 5.42 (t, J =6.7 Hz, 1H), 5.14 (d, J = 10.0 Hz, 1H), 4.04 (t, J = 5.0 Hz, 2H),3.78-3.66 (m, 1H), 3.37-3.20 (m, 6H), 3.18-3.10 (m, 2H), 3.09-2.97 (m,1H), 2.37-2.30 (m, 1H), 2.08-1.96 (m, 2H), 1.94-1.80 (m, 6H), 1.72-1.62(m, 8H), 1.58-1.47 (m, 1H), 1.43-1.33 (m, 2H)

Procedure 2. Preparation of(S)-2-hydroxy-2-(3-hydroxyphenyl)-2-phenylacetic acid and(R)-2-hydroxy-2-(3-hydroxyphenyl)-2-phenylacetic acid

Step 1; (3-Bromophenoxy)(tert-butyl)dimethylsilane

A solution of 3-bromophenol (100.00 g, 580 mmol) and imidazole (78.70 g,1.16 mmol) in DCM (1.2 L) was added drop-wise to a cooled (ice/NaClbath) solution of tert-butyldimethylsilyl chloride (95.83 g, 630 mmol)in DCM (100 mL). The reaction mixture was stirred at room temperaturefor 16 hours. The reaction mixture was washed with water, brine and theorganic phase was evaporated under reduced pressure. The residue waspurified by flash column chromatography (eluent—100% iso-hexane to 5:1iso-hexane/ethyl acetate) to afford the title product (163.7 g, 99%).

¹H NMR (400 MHz, CDCl₃) δ 7.12-7.10 (m, 2H), 7.03 (ddd, J=2.2, 1.4, 0.8Hz, 1H), 6.81-6.76 (m, 1H), 1.00 (s, 9H), 0.22 (s, 6H).

Step 2; (R)-Quinuclidin-3-yl 2-oxo-2-phenylacetate

Benzoylformic acid (50.00 g, 0.33 mol) was dissolved in chloroform (400mL) and oxalyl chloride (40.02 mL, 0.47 mol) was added drop-wise at roomtemperature. The reaction mixture stirred for 1 hour and the solventevaporated under reduced pressure. The residue was dissolved inchloroform (305 mL) and cooled to 0° C. A solution of3-(R)-quinuclidinol (50.83 g, 0.40 mmol) in chloroform (200 mL) wasadded drop-wise. The reaction mixture was allowed warm to roomtemperature and stirred for 1 hour. The reaction mixture was cooled to0° C. and quenched with 10% aqueous potassium carbonate solution. Theorganic layer was separated and washed with water (2×), brine (3×) anddried over anhydrous magnesium sulfate. The filtrate was evaporatedunder reduced pressure to afford the title compound (77.2 g, 89%).

¹H NMR (400 MHz, DMSO-d₆) δ 8.01-7.95 (m, 2H), 7.84-7.77 (m, 1H),7.68-7.61 (m, 2H), 5.15-5.05 (m, 1H), 3.26 (dd, J=14.7, 8.2 Hz, 1H),2.79-2.58 (m, 5H), 2.13-2.04 (m, 1H), 1.72-1.53 (m, 3H), 1.42-1.33 (m,1H).

Step 3; (R)-Quinuclidin-3-yl2-(3-((tert-butyldimethylsilyl)oxy)phenyl)-2-hydroxy-2-phenylacetate

Magnesium turnings (8.58 g, 0.36 mol, 1.5 eq) and iodine (catalytic)were suspended in anhydrous THF (460 mL) under argon and a solution of(3-bromophenoxy)(tert-butyl)dimethylsilane (88.01 g, 0.306 mol, 1.2 eq)in anhydrous THF (175 mL) added drop-wise. The reaction mixture wasstirred at reflux for 2 hours. The reaction mixture was cooled to roomtemperature and then added drop-wise via a syringe pump to a solution of(R)-quinuclidin-3-yl 2-oxo-2-phenylacetate (66.2 g, 0.26 mol, 1 eq) inanhydrous THF (660 mL) at −75° C. over 2 hours. The reaction mixture wasallowed to warm to room temperature and then stirred overnight. Thereaction mixture was cooled to 0° C. and quenched with saturated aqueousammonium chloride (500 mL). The reaction mixture was extracted withethyl acetate and the organic phase was washed with brine, dried overanhydrous magnesium sulfate and the filtrate evaporated under reducedpressure. The residue was purified by flash column chromatography(eluent—100% DCM to 20:1 DCM/methanol) to afford the title product (66.2g, 78.5%).

¹H NMR (400 MHz, DMSO-d₆) δ 7.37-7.28 (m, 5H), 7.25-7.20 (m, 1H),7.01-6.95 (m, 1H), 6.83-6.76 (m, 2H), 6.60 (s, 1H), 4.84-4.78 (m, 1H),3.12-3.06 (m, 1H), 2.65-2.56 (m, 3H), 2.48-2.37 (m, 2H), 1.90-1.80 (m,1H), 1.59-1.42 (m, 2H), 1.36-1.30 (m, 1H), 1.21-1.12 (m, 1H), 0.92-0.89(m, 9H), 0.12 (d, J=1.0 Hz, 6H).

Step 4; (R)-Quinuclidin-3-yl2-hydroxy-2-(3-hydroxyphenyl)-2-phenylacetate

(R)-Quinuclidin-3-yl2-(3-((tert-butyldimethylsilyl)oxy)phenyl)-2-hydroxy-2-phenylacetate(93.72 g, 200 mmol) was dissolved in THF (937 mL) and TBAF*3H2O (69.54g, 11.5 mmol) was added and the reaction mixture was stirred at roomtemperature for 1 hour. THF was evaporated and the resulting crude wasdissolved in ethyl acetate and washed with 0.5M hydrochloric acid (3×350mL). The combined aqueous layers were neutralized with sodium hydrogencarbonate (to pH 8). The resulting precipitate was filtered to give26.05 g HPLC 100% (51.9:48.1). Aqueous layer (filtrate) was washed withethyl acetate (3×1 L) and the combined organic layers were concentratedto give desired product (38.64 g, yield 55.6, 75:25 ratio).

Method 10. Chiral-HPLC

First diastereoisomer rt 12.18 minSecond diastereoisomer rt 12.87 min

Step 5; (S,R)- and (R,R)-Quinuclidin-3-yl2-hydroxy-2-(3-hydroxyphenyl)-2-phenylacetate

(R)-Quinuclidin-3-yl2-(3-((tert-butyldimethylsilyl)oxy)phenyl)-2-hydroxy-2-phenylacetate (26g, 1:1 ratio) was purified via flash column chromatography (25 g SiO₂/1g crude, eluent: DCM; Acetone; TEA; 7:2.5:0.5) leading to

i) (S)—(R)-quinuclidin-3-yl2-hydroxy-2-(3-hydroxyphenyl)-2-phenylacetate (7.00 g, de=99.2%).

Method 9 HPLC-AB: t_(R) 12.1 min.

ii) (R)—(R)-quinuclidin-3-yl2-hydroxy-2-(3-hydroxyphenyl)-2-phenylacetate (1.7 g, de=95%).

Method 9 HPLC-AB: t_(R) 12.5 min.

The absolute configuration of the unknown stereogenic center wasassigned by single crystal X-ray diffraction.

Step 6; (S)-2-Hydroxy-2-(3-hydroxyphenyl)-2-phenylacetic acid

To a solution of (S)—(R)-quinuclidin-3-yl2-hydroxy-2-(3-hydroxyphenyl)-2-phenylacetate (28.24 g, 79.91 mmol) inmethanol (282.40 mL, 10 vol at 0° C., aqueous 2M sodium hydroxide (79.91ml, 159.89 mmol) was added drop-wise. The reaction mixture was heated toreflux and stirred for 30 min. The solvent was evaporated and thereaction mixture adjusted to pH-8 with 1M hydrochloric acid and washedwith ethyl acetate (2×100 mL). The aqueous layer was acidified with 1Mhydrochloric acid to pH 4-5 and extracted with ethyl acetate (3×250 mL).The combined organic extracts were dried (magnesium sulfate),concentrated and then dried under vacuum for 3 day at 35° C. to give thetitle compound (17.58 g, 90% yield).

¹H NMR (400 MHz, DMSO-d₆) δ 13.12 (bs, 1H), 9.33 (bs, 1H), 7.41-7.25 (m,5H), 7.14-7.07 (m, 1H), 6.84-6.78 (m, 2H), 6.69-6.64 (m, 1H).

Method 10 Chiral HPLC: t_(R) 12.95 min

Procedure 3. Preparation of (S)-tert-butyl4-((2-(3-(benzyloxy)phenyl)-2-hydroxy-2-phenylacetoxy)methyl)piperidine-1-carboxylateand (R)-tert-butyl4-((2-(3-(benzyloxy)phenyl)-2-hydroxy-2-phenylacetoxy)methyl)piperidine-1-carboxylateStep 1; 2-(3-(Benzyloxy)phenyl)-2-hydroxy-2-phenylacetic acid

A stirred solution of ethyl2-(3-(benzyloxy)phenyl)-2-hydroxy-2-phenylacetate (as described inExample 1, Step 1) (20.3 g, 56.1 mmol) in THF (100 mL) was added withaqueous 2M sodium hydroxide (20 mL). The reaction mixture was stirred atroom temperature for 2 hours and then the solvent removed under reducedpressure. The pH was adjusted to 1 with aqueous 1M hydrochloric acid andthen extracted with ethyl acetate (×2). The combined organic extractswere washed with brine, dried over anhydrous magnesium sulfate and thefiltrate evaporated under reduced pressure to afford the title product(18.4 g, 98%).

¹H NMR (400 MHz, DMSO-d₆); δ 7.45-7.23 (m, 11H), 7.02 (dd, J=2.1, 2.1Hz, 1H), 6.98-6.93 (m, 2H), 5.05 (s, 2H), 3.34 (s, 1H).

Step 2; tert-Butyl4-((2-(3-(benzyloxy)phenyl)-2-hydroxy-2-phenylacetoxy)methyl)piperidine-1-carboxylate

A stirred solution of 2-(3-(benzyloxy)phenyl)-2-hydroxy-2-phenylaceticacid (10.1 g, 30.2 mmol) in DMF (100 mL) was added with potassiumcarbonate (5.0 g, 36.2 mmol). After 10 minutes tert-butyl4-(tosyloxymethyl)piperidine-1-carboxylate (as described in Example 1,Step 5) (11.1 g, 30.2 mmol) was added and the resulting mixture heatedat 80° C. for 18 hours. The reaction mixture was diluted with ethylacetate and washed with water and brine (×2). The organic phase wasdried over anhydrous magnesium sulfate and the filtrate was evaporatedunder reduced pressure. The residue was purified by flash columnchromatography (eluent—100% iso-hexane to 4:1 iso-hexane/ethyl acetate)to afford the title compound (9.51 g, 59%).

¹H NMR (400 MHz, CDCl₃); δ 7.42-7.24 (m, 11H), 7.08 (dd, J=2.1, 2.1 Hz,1H), 6.99 (d, J=7.8 Hz, 1H), 6.93 (dd, J=2.4, 8.4 Hz, 1H), 5.02 (s, 2H),4.21 (s, 1H), 4.12-4.03 (m, 4H), 2.63-2.57 (m, 2H), 1.79-1.69 (m, 1H),1.50-1.40 (m, 11H), 1.09-0.89 (m, 2H).

Step 3; (S)-tert-Butyl4-((2-(3-(benzyloxy)phenyl)-2-hydroxy-2-phenylacetoxy)methyl)piperidine-1-carboxylateand (R)-tert-butyl4-((2-(3-(benzyloxy)phenyl)-2-hydroxy-2-phenylacetoxy)methyl)piperidine-1-carboxylate

tert-Butyl4-((2-(3-(benzyloxy)phenyl)-2-hydroxy-2-phenylacetoxy)methyl)-piperidine-1-carboxylatewas separated by chiral SFC.

SFC method:

Instrument: Waters Prep 100

Column: YMC Amylose-C

Eluant; 30/70 iso-propyl alcohol/CO₂ at a flow rate of 100 ml/min 120bar and 40° C.

Example 4. (S)-(1-Benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-((5-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)pentyl)oxy)phenyl)-2-phenylacetate(Compound 13)

Step 1; (S)-4-(1,3-Dioxolan-2-yl)butyl2-(3-(4-(1,3-dioxolan-2-yl)butoxy)phenyl)-2-hydroxy-2-phenylacetate

A stirred solution of (S)-2-hydroxy-2-(3-hydroxyphenyl)-2-phenylaceticacid (1.90 g, 7.78 mmol) in DMF (30 mL) was added with potassiumcarbonate (3.22 g, 23.3 mmol). To this mixture was added2-(4-chlorobutyl)-1,3-dioxolane (2.89 mL, 19.45 mmol) and the reactionmixture heated at 85° C. for 72 hours. The reaction mixture was dilutedwith ethyl acetate and washed with water and brine (×2). The organicphase was dried over anhydrous magnesium sulfate and the filtrate wasevaporated under reduced pressure. The residue was purified by flashcolumn chromatography (eluent—100% iso-hexane to 1:1 iso-hexane/ethylacetate) to afford the title compound (2.8 g, 72%).

¹H NMR (400 MHz, DMSO-d₆); δ 7.33 (d, J=4.1 Hz, 6H), 6.89-6.85 (m, 3H),6.57 (s, 1H), 4.78 (dd, J=4.8, 4.8 Hz, 1H), 4.69 (dd, J=4.8, 4.8 Hz,1H), 4.14 (dd, J=6.4, 6.4 Hz, 2H), 3.93-3.71 (m, 10H), 1.74-1.44 (m,10H), 1.32-1.16 (m, 2H).

Step 2;(S)-2-(3-(4-(1,3-Dioxolan-2-yl)butoxy)phenyl)-2-hydroxy-2-phenylaceticacid

A stirred solution of (S)-4-(1,3-dioxolan-2-yl)butyl2-(3-(4-(1,3-dioxolan-2-yl)butoxy)phenyl)-2-hydroxy-2-phenylacetate (2.8g, 5.59 mmol) in THF (25 mL) was added aqueous with 2M sodium hydroxide(25 mL). The reaction mixture was stirred at room temperature for 1hour. The organic solvent was evaporated under reduced pressure. Theaqueous residue was washed with ether and the pH of the aqueous phaseadjusted to 5 with aqueous 1M hydrochloric acid. The mixture wasextracted with ethyl acetate and the organic phase washed with water andbrine (×2). The organic phase was dried over anhydrous magnesium sulfateand the filtrate was evaporated under reduced pressure. The residue waspurified by flash column chromatography (eluent—100% iso-hexane to 1:1iso-hexane/ethyl acetate) to afford the title compound (1.46 g, 70%).

¹H NMR (400 MHz, DMSO-d₆); δ 7.45-7.25 (m, 6H), 7.01-6.96 (m, 2H),6.91-6.88 (m, 1H), 6.40 (br s, 1H), 4.83 (dd, J=4.8, 4.8 Hz, 1H),3.98-3.78 (m, 6H), 1.81-1.62 (m, 4H), 1.57-1.49 (m, 2H).

Step 3; (S)-(1-Benzylpiperidin-4-yl)methyl2-(3-(4-(1,3-dioxolan-2-yl)butoxy)phenyl)-2-hydroxy-2-phenylacetate

A stirred solution of(S)-2-(3-(4-(1,3-dioxolan-2-yl)butoxy)phenyl)-2-hydroxy-2-phenylaceticacid (0.119 g, 0.32 mmol) in DMF (2 mL) was added with carbonyldiimidazole (0.078 g, 0.48 mmol) and the mixture heated at 50° C. for 30minutes. A solution of N-benzyl piperidine-4-methanol (0.098 g, 0.32mmol) in DMF (0.5 mL) was added and the mixture heated at 50° C. for 18hours. The reaction mixture was diluted with ethyl acetate and washedwith water and brine (×2). The organic phase was dried over anhydrousmagnesium sulfate and the filtrate was evaporated under reducedpressure. The residue was purified by reverse phase columnchromatography to afford the title compound (0.075 g, 38%).

¹H NMR (400 MHz, CDCl₃,); δ 7.42-7.38 (m, 2H), 7.35-7.19 (m, 9H),7.00-6.94 (m, 2H), 6.83 (ddd, J=8.2, 2.5, 0.9 Hz, 1H), 5.30 (s, 2H),4.88-4.83 (m, 1H), 4.22 (s, 1H), 4.15-4.06 (m, 2H), 4.01-3.80 (m, 6H),3.45 (s, 2H), 2.81 (d, J=11.3 Hz, 2H), 1.92-1.66 (m, 6H), 1.70-1.46 (m,3H), 1.28-1.13 (m, 2H).

Step 4; (Compound 13)

The title compound (13) was prepared as described in Example 1 Step 9

Salt 2 eq N R_(t) (min) Method NMR data (400 MHz) unless stated 113 2.328 (DMSO-d6, 90° C.); δ 8.15 (d, J = 9.2 Hz, 1H), 7.48 (m, 4H), 7.35-7.31(m, TFA 5H), 7.24 (dd, J = 7.9, 7.9 Hz, 1H), 7.15 (d, J = 8.2 Hz, 1H),6.99 (d, J = 8.2 Hz, 1H), 6.89-6.85 (m, 3H), 6.63-6.57 (m, 2H), 5.30 (d,J = 9.8 Hz, 1H), 4.31-4.21 (m, 3H), 4.01 (d, J = 6.4 Hz, 2H), 3.90 (dd,J = 6.2, 6.2 Hz, 2H), 3.34 (d, J = 11.3 Hz, 2H), 3.10-2.97 (m, 5H), 2.90(d, J = 12.4 Hz, 2H), 1.85 (m, 1H), 1.71-1.65 (m, 5H), 1.47-1.30 (m,4H).

The following compounds were prepared as described in Example 4 with therelevant (R) or (S) stereoisomer of2-hydroxy-2-(3-hydroxyphenyl)-2-phenylacetic acid used in Step 1 and therequired commercially available amine replacing N-benzylpiperidine-4-methanol in Step 3.

Compound number Relevant stereoisomer Amine Structure 14

15

16

17

18

19

20

21

22

23

24

25

26

Salt (2 eq N Rt (min) Method NMR data (400 MHz) unless stated) 14 7.19 7(DMSO-d₆); δ 10.54 (d, J = 15.7 Hz, 2H), 9.44 (s, 1H), 8.61-8.60 (m,2H), 8.20 (d, TFA J = 11.6 Hz, 1H), 7.53 (s, 5H), 7.40-7.36 (m, 6H),7.20 (d, J = 8.3 Hz, 1H), 7.04 (d, J = 8.1 Hz, 1H), 6.95-6.90 (m, 3H),6.69-6.62 (m, 2H), 6.21 (s, 1H), 5.37-5.34 (m, 1H), 4.37-4.26 (m, 3H),4.06 (d, J = 6.3 Hz, 2H), 3.95 (dd, J = 6.2, 6.2 Hz, 2H), 3.38 (d, J =10.9 Hz, 2H), 3.16-2.90 (m, 5H), 1.93-1.88 (m, 1H), 1.83-1.71 (m, 6H),1.53-1.34 (m, 4H) 15 6.94 7 (DMSO-d₆); δ 10.54 (d, J = 15.9 Hz, 2H),9.66 (s, 1H), 8.60-8.60 (m, 2H), 8.21 (d, TFA J = 10.4 Hz, 1H), 7.41 (d,J = 4.5 Hz, 4H), 7.40-7.35 (m, 1H), 7.31 (dd, J = 8.0, 8.0 Hz, 1H), 7.20(d, J = 8.1 Hz, 1H), 7.05-6.91 (m, 4H), 6.81 (s, 1H), 6.64 (dd, J = 1.9,10.0 Hz, 1H), 6.20 (d, J = 2.0 Hz, 1H), 5.35 (d, J = 9.6 Hz, 1H),5.21-5.19 (m, 1H), 3.97 (dd, J = 6.2, 6.2 Hz, 2H), 3.78-3.70 (m, 1H),3.28-2.98 (m, 9H), 2.27 (d, J = 2.5 Hz, 1H), 1.95-1.87 (m, 2H),1.79-1.61 (m, 6H), 1.53-1.44 (m, 2H) 16 6.95 7 (DMSO-d₆); δ 10.54 (d, J= 12.9 Hz, 2H), 9.74-9.71 (m, 1H), 8.61-8.60 (m, 2H), TFA 8.21 (d, J =9.0 Hz, 1H), 7.44-7.30 (m, 6H), 7.20 (d, J = 8.1 Hz, 1H), 7.02 (dd, J =8.1, 14.9 Hz, 2H), 6.95-6.91 (m, 2H), 6.81 (s, 1H), 6.64 (dd, J = 1.9,10.0 Hz, 1H), 6.22 (s, 1H), 5.35 (d, J = 9.6 Hz, 1H), 5.23-5.18 (m, 1H),3.97 (t, J = 6.7 Hz, 2H), 3.74 (td, J = 5.2, 17.9 Hz, 1H), 3.27-2.98 (m,9H), 2.27 (d, J = 3.0 Hz, 1H), 1.96-1.86 (m, 2H), 1.79-1.61 (m, 6H),1.53-1.43 (m, 2H) 17 2.14 8 (DMSO-d₆); δ 10.50 (d, J = 18.1 Hz, 2H),9.59 (s, 1H), 8.56-8.56 (m, 2H), 8.15 (d, TFA J = 10.7 Hz, 1H), 7.35 (m,6H), 7.15 (d, J = 8.3 Hz, 1H), 6.98 (d, J = 8.2 Hz, 1H), 6.94 (d, J =8.2 Hz, 1H), 6.89-6.87 (m, 2H), 6.68 (s, 1H), 6.59 (dd, J = 2.1, 9.9 Hz,1H), 6.17 (d, J = 3.4 Hz, 1H), 5.31-5.28 (m, 1H), 4.47 (dd, J = 5.0, 5.0Hz, 2H), 3.97-3.88 (m, 2H), 3.14-2.98 (m, 6H), 2.69 (s, 6H), 1.74-1.64(m, 4H), 1.48-1.40 (m, 2H). 18 6.89 7 (DMSO-d₆); δ 10.49 (d, J = 14.1Hz, 2H), 9.62 (s, 1H), 8.57-8.56 (m, 2H), 8.15 (d, TFA J = 9.9 Hz, 1H),7.35 (d, J = 4.3 Hz, 4H), 7.33-7.23 (m, 2H), 7.15 (d, J = 8.2 Hz, 1H),6.98 (d, J = 8.2 Hz, 1H), 6.93 (d, J = 8.0 Hz, 1H), 6.90-6.87 (m, 2H),6.67 (s, 1H), 6.59 (dd, J = 1.8, 9.9 Hz, 1H), 6.17-6.16 (m, 1H), 5.30(d, J = 9.4 Hz, 1H), 4.47 (dd, J = 5.1, 5.1 Hz, 2H), 3.91 (dd, J = 6.3,6.3 Hz, 2H), 3.40 (s, 2H), 3.14-3.04 (m, 2H), 3.01-2.95 (m, 2H), 2.69(s, 6H), 1.75-1.64 (m, 4H), 1.48-1.40 (m, 2H). 19 6.90 7 (DMSO-d₆); δ10.54 (d, J = 13.9 Hz, 2H), 10.17 (s, 1H), 8.62-8.60 (m, 2H), 8.20 (d,TFA J = 11.5 Hz, 1H), 7.41-7.28 (m, 6H), 7.20 (d, J = 10.2 Hz, 1H),7.05-6.97 (m, 2H), 6.93 (m, 2H), 6.64 (d, J = 8.9 Hz, 2H), 6.21 (s, 1H),5.50 (d, J = 16.6 Hz, 1H), 5.36 (d, J = 8.9 Hz, 1H), 3.97 (dd, J = 6.2,6.2 Hz, 2H), 3.61 (m, 4H), 3.18-3.01 (m, 4H), 2.95-2.72 (m, 3H), 2.5-2.3(m, 1H), 2.1-1.9 (m, 1H), 1.81-1.69 (m, 4H), 1.53-1.44 (m, 2H). 20 6.907 (DMSO-d₆); δ 10.49 (d, J = 13.2 Hz, 2H), 10.15 (s, 1H), 8.57 (s, 2H),8.15 (d, J = 9.9 Hz, TFA 1H), 7.35 (d, J = 3.3 Hz, 4H), 7.33-7.23 (m,2H), 7.15 (d, J = 8.2 Hz, 1H), 7.00-6.92 (m, 2H), 6.88 (d, J = 7.5 Hz,2H), 6.59 (dd, J = 1.8, 9.8 Hz, 2H), 6.17-6.17 (m, 1H), 5.44 (d, J =22.5 Hz, 1H), 5.31 (d, J = 9.2 Hz, 1H), 3.92 (t, J = 5.4 Hz, 2H), 3.59(m, 2H), 3.41-3.40 (m, 0.5H), 3.13-2.97 (m, 5H), 2.77 (d, J = 63.6 Hz,4H), 2.25 (m, 0.5H), 2.09-2.08 (m, 0.5H), 1.91 (m, 0.5H), 1.74-1.64 (m,4H), 1.48-1.40 (m, 2H). 21 6.89 7 (DMSO-d₆, 90° C.); δ 8.18 (d, J = 9.9Hz, 1H), 7.42-7.24 (m, 6H), 7.15 (d, J = 8.2 Hz, TFA 1H), 7.03-6.94 (m,3H), 6.89 (dd, J = 2.2, 8.1 Hz, 1H), 6.56 (d, J = 9.8 Hz, 1H), 5.35 (dd,J = 4.4, 8.4 Hz, 1H), 5.09 (s, 1H), 3.95 (dd, J = 6.3, 6.3 Hz, 2H),3.19-3.00 (m, 8H), 2.71 (s, 3H), 2.11-2.06 (m, 2H), 1.78-1.70 (m, 6H),1.53-1.46 (m, 2H). 22 6.90 7 (DMSO-d₆, 90° C.); δ 8.19 (d, J = 9.9 Hz,1H), 7.42-7.22 (m, 6H), 7.15 (d, J = 8.2 Hz, TFA 1H), 7.02 (d, J = 8.2Hz, 1H), 6.96 (d, J = 8.0 Hz, 2H), 6.90-6.85 (m, 1H), 6.55 (d, J = 9.9Hz, 1H), 5.36 (dd, J = 4.5, 8.3 Hz, 1H), 5.07 (d, J = 1.9 Hz, 1H), 3.95(dd, J = 6.3, 6.3 Hz, 2H), 3.19-3.00 (m, 8H), 2.70 (s, 3H), 2.05 (d, J =8.9 Hz, 2H), 1.86-1.84 (m, 2H), 1.79-1.67 (m, 4H), 1.53-1.45 (m, 2H). 236.96 7 (DMSO-d₆, 90° C.); δ 8.19 (d, J = 9.9 Hz, 1H), 7.40-7.22 (m, 6H),7.15 (d, J = 8.2 Hz, TFA 1H), 7.02 (d, J = 8.0 Hz, 1H), 6.96-6.94 (m,2H), 6.88-6.86 (m, 1H), 6.56 (d, J = 9.9 Hz, 1H), 6.26-6.26 (m, 1H),5.35 (dd, J = 4.5, 8.4 Hz, 1H), 4.09 (d, J = 6.5 Hz, 2H), 3.96 (dd, J =6.4, 6.4 Hz, 2H), 3.31 (d, J = 11.0 Hz, 2H), 3.16-2.96 (m, 6H), 2.73 (s,3H), 1.92-1.85 (m, 1H), 1.78-1.71 (m, 6H), 1.54-1.42 (m, 4H). 24 6.97 7(DMSO-d₆); δ 8.30 (s, 2H), 8.19 (d, J = 9.6 Hz, 1H), 7.33-7.31 (m, 6H),7.11 (d, Formate J = 8.3 Hz, 1H), 6.96 (d, J = 8.2 Hz, 1H), 6.90-6.85(m, 3H), 6.53 (d, J = 9.8 Hz, 1H), 5.20 (dd, J = 4.3, 8.4 Hz, 1H), 3.99(d, J = 6.0 Hz, 2H), 3.90 (dd, J = 6.3, 6.3 Hz, 2H), 2.90-2.68 (m, 5H),2.13 (s, 3H), 1.84-1.77 (m, 2H), 1.74-1.64 (m, 2H), 1.61-1.39 (m, 8H),1.18-1.09 (m, 2H). 25 6.95 7 (DMSO-d₆, 90° C.); δ 8.18 (d, J = 10.5 Hz,1H), 7.43-7.31 (m, 5H), 7.25 (dd, J = 8.0, TFA 8.0 Hz, 1H), 7.15 (d, J =8.2 Hz, 1H), 7.03-6.94 (m, 3H), 6.87 (dd, J = 2.4, 8.3 Hz, 1H), 6.57 (d,J = 9.8 Hz, 1H), 5.33 (dd, J = 4.5, 8.5 Hz, 1H), 5.16 (m, 1H), 4.00-3.93(m, 2H), 3.17-3.01 (m, 10H), 2.74 (s, 3H), 1.78-1.69 (m, 6H), 1.53-1.45(m, 2H). 26 6.87 7 (DMSO-d₆, 90° C.); δ 8.19 (d, J = 9.9 Hz, 1H), 7.42(dd, J = 1.5, 8.3 Hz, 2H), TFA 7.38-7.24 (m, 4H), 7.15 (d, J = 8.2 Hz,1H), 7.03-6.95 (m, 3H), 6.88 (dd, J = 2.3, 8.0 Hz, 1H), 6.56 (d, J = 9.9Hz, 1H), 5.37-5.31 (m, 2H), 4.43-4.37 (m, 2H), 3.99-3.88 (m, 4H),3.22-3.11 (m, 2H), 3.07-3.01 (m, 2H), 2.80 (s, 3H), 1.78-1.69 (m, 4H),1.53-1.44 (m, 2H).

The following compounds were prepared as described in Example 4 with therelevant (R) or (S) stereoisomer of2-hydroxy-2-(3-hydroxyphenyl)-2-phenylacetic acid used in Step 1 and theappropriate alkylating agent replacing 2-(4-chlorobutyl)-1,3-dioxolanein Step 1.

Alkylating N Relevant stereoisomer Agent Structure 27

28

29

30

Salt (2 eq N Rt (min) Method NMR data (400 MHz) unless stated) 27 715 7(DMSO-d₆); δ 10.54 (s, 1H), 10.49 (s, 1H), 9.56 (s, 1 H), 8.61-8.61 (m,2H), TFA 8.16 (d, J = 9.9 Hz, 1H), 7.47 (s, 5H), 7.35-7.31 (m, 6H), 7.15(d, J = 8.0 Hz, 1H), 7.03-6.97 (m, 1H), 6.90-6.83 (m, 3H), 6.62 (s, 1H),6.58 (d, J = 9.9 Hz, 1H), 6.18-6.18 (m, 1H), 5.31 (d, J = 9.2 Hz, 1H),4.25-4.21 (m, 2H), 4.01 (d, J = 6.4 Hz, 2H), 3.90 (dd, J = 6.3, 6.3 Hz,2H), 3.08 (m, 4H), 2.97-2.88 (m, 4H), 1.75-1.61 (m, 7H), 1.36 (dd, J =11.5, 11.5 Hz, 6H). 28 7.34 77 (DMSO-d₆); δ 10.50 (m, 2H), 9.51 (s, 1H),8.58 (s, 2H), 8.16 (d, J = 9.9 Hz, TFA 1H), 7.47 (s, 5H), 7.33 (s, 5H),7.23 (dd, J = 8.0, 8.0 Hz, 1H), 7.15 (d, J = 8.2 Hz, 1H), 6.99 (d, J =8.2 Hz, 1H), 6.90-6.85 (m, 3H), 6.64-6.57 (m, 2H), 6.18 (d, J = 2.5 Hz,1H), 5.31 (d, J = 9.0 Hz, 1H), 4.27-4.23 (m, 2H), 4.01 (d, J = 6.3 Hz,2H), 3.90 (dd, J = 6.4, 6.4 Hz, 2H), 2.98-2.98 (m, 10H), 1.68-1.64 (m,5H), 1.38-1.31 (m, 8H) 29 7.44 77 (DMSO-d₆); δ 10.51 (s, 2H), 9.56 (s,1H), 8.61 (s, 2H), 8.16 (d, J = 9.9 Hz, TFA 1H), 7.48 (s, 5H), 7.33-722(m, 6H), 7.15 (d, J = 8.2 Hz, 1H), 6.99 (d, J = 8.2 Hz, 1H), 6.90-6.83(m, 3H), 6.59 (t, J = 11.1 Hz, 2H), 6.18 (s, 1H), 5.31 (d, J = 8.8 Hz,1H), 4.28-4.21 (m, 2H), 4.01 (d, J = 6.3 Hz, 2H), 3.90 (dd, J = 6.1, 6.1Hz, 2H), 3.14-2.85 (m, 7H), 1.75-1.62 (m, 7H), 1.40-1.34 (m, 7H). 307.43 77 (DMSO-d₆); δ 10.53 (d, J = 21.3 Hz, 2H), 9.79 (s, 1H), 8.76 (s,1H), 8.61 (s, TFA 1H), 8.19 (d, J = 12.0 Hz, 1H), 7.49-7.46 (m, 5H),7.35-7.31 (m, 6H), 7.15 (d, J = 8.3 Hz, 1H), 7.00 (d, J = 8.2 Hz, 1H),6.87 (d, J = 8.4 Hz, 3H), 6.62 (s, 1H), 6.57 (d, J = 9.8 Hz, 1H), 6.19(s, 1H), 5.34 (d, J = 8.0 Hz, 1H), 4.29-4.20 (m, 2H), 4.00 (d, J = 6.4Hz, 2H), 3.89 (dd, J = 6.4, 6.4 Hz, 2H), 3.11-2.83 (m, 7H), 1.83-1.64(m, 8H), 1.43-1.23 (m, 10H).

Procedure 4

Preparation of(R)-4-(((tert-butoxycarbonyl)(2-((tert-butyldimethylsilyl)oxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzoicacid

Step 1;(R)-5-(2-amino-1-((tert-butyldimethylsilyl)oxy)ethyl)-8-(benzyloxy)quinolin-2(1H)-one

A solution of(R)-5-(2-azido-1-((tert-butyldimethylsilyl)oxy)ethyl)-8-(benzyloxy)quinolin-2(1H)-one(3.83 g, 8.5 mmol) in THF/water (30 mL/1 mL) was added with polymersupported triphenylphosphine (7.3 g, 1.4 mmol/g loading, 10.2 mmol). Thereaction mixture was heated at reflux with no stirring for 18 hours. Thesuspension was filtered, the filter cake was washed with ethyl acetateand the filtrate was evaporated under reduced pressure to afford thetitle compound. The material was used directly in the next step with nopurification.

Step 2; (R)-Methyl4-(((2-(8-(benzyloxy)-2-oxo-1,2-dihydroquinolin-5-yl)-2-((tert-butyldimethylsilyl)oxy)ethyl)amino)methyl)benzoate

A stirred mixture of(R)-5-(2-amino-1-((tert-butyldimethylsilyl)oxy)ethyl)-8-(benzyloxy)quinolin-2(1H)-one(2.9 g, 6.83 mmol) and methyl 4-formylbenzoate (1.23 g, 7.49 mmol) inDCM (30 mL) was added with anhydrous magnesium sulfate and the mixturestirred at room temperature for 18 hours. The suspension was filteredthrough a plug of anhydrous magnesium sulfate, the filter cake waswashed with further DCM and the filtrate was evaporated under reducedpressure. The residue was dissolved in methanol (30 mL) and the mixturecooled to 0° C. Sodium borohydride (0.517 g, 13.7 mmol) was addedportion wise and the reaction mixture stirred at 0° C. for 30 minutes.The coolant was removed and the mixture stirred at room temperature fora further 2 hours. The mixture was quenched with 10% aqueous potassiumcarbonate and extracted with DCM (×2). The combined DCM extracts werewashed with brine, dried over anhydrous magnesium sulfate and thefiltrate was evaporated under reduced pressure. The residue was purifiedby flash column chromatography (eluent—100% DCM to 25:1 DCM/methanol) toafford the title compound (3.26 g, 83%).

¹H NMR (400 MHz, DMSO-d₆) δ 10.51 (s, 1H), 8.20 (d, J=9.9 Hz, 1H), 7.81(d, J=8.3 Hz, 2H), 7.52 (d, J=7.2 Hz, 2H), 7.36-7.31 (m, 4H), 7.29-7.25(m, 1H), 7.15 (d, J=8.3 Hz, 1H), 7.07 (d, J=8.4 Hz, 1H), 6.46 (d, J=9.9Hz, 1H), 5.23 (s, 2H), 5.13 (dd, J=4.7, 7.2 Hz, 1H), 3.80-3.78 (m, 3H),3.73 (s, 2H), 2.72 (dd, J=7.8, 12.0 Hz, 1H), 2.63-2.55 (m, 1H), 0.77 (s,9H), 0.00 (s, 3H), −0.21 (s, 3H).

Step 3; (R)-Methyl4-(((2-(8-(benzyloxy)-2-oxo-1,2-dihydroquinolin-5-yl)-2-((tert-butyldimethylsilyl)oxy)ethyl)(tert-butoxycarbonyl)amino)methyl)benzoate

A stirred solution of (R)-methyl4-(((2-(8-(benzyloxy)-2-oxo-1,2-dihydroquinolin-5-yl)-2-((tert-butyldimethylsilyl)oxy)ethyl)amino)methyl)benzoate(3.25 g, 5.67 mmol) in DCM (25 mL) was added with a solution ofdi-tert-butyl dicarbonate (1.49 g, 6.83 mmol) in DCM (5 mL). Thereaction mixture was stirred at room temperature for 18 hours. Thesolvent was evaporated under reduced pressure and the residue purifiedby flash column chromatography (eluent—100% iso-hexane to 3:2iso-hexane/ethyl acetate) to afford the title compound (2.84 g, 75%).

LCMS (Method 11); Rt 4.33 min; M+1 673.4

Step 4;(R)-4-(((2-(8-(Benzyloxy)-2-oxo-1,2-dihydroquinolin-5-yl)-2-((tert-butyldimethylsilyl)oxy)ethyl)(tert-butoxycarbonyl)amino)methyl)benzoicacid

A stirred solution of (R)-methyl4-(((2-(8-(benzyloxy)-2-oxo-1,2-dihydroquinolin-5-yl)-2-((tert-butyldimethylsilyl)oxy)ethyl)(tert-butoxycarbonyl)-amino)methyl)benzoate(2.84 g, 4.22 mmol) in methanol (10 mL) was added with aqueous 2M sodiumhydroxide (10 mL). The reaction mixture was then stirred at roomtemperature for 18 hours. The solvent was evaporated under reducedpressure and the residue partitioned between DCM and 10% aqueouspotassium hydrogen sulfate. The organic phase was removed and theaqueous phase extracted with further DCM. The combined DCM extracts werewashed with brine, dried over anhydrous magnesium sulfate and thefiltrate was evaporated under reduced pressure to afford the titlecompound (2.58 g, 93%).

LCMS (Method 11); Rt 4.05 min; M+1 659

Step 5;(R)-4-(((tert-Butoxycarbonyl)(2-((tert-butyldimethylsilyl)oxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzoicacid

10% Palladium on carbon (2 g) was added to a stirred solution of(R)-4-(((2-(8-(benzyloxy)-2-oxo-1,2-dihydroquinolin-5-yl)-2-((tert-butyldimethylsilyl)oxy)ethyl)(tert-butoxycarbonyl)amino)methyl)benzoicacid (2.06 g, 3.12 mmol) in ethanol (25 mL) under an inert nitrogenatmosphere. 1-Methyl-1,4-cyclohexadiene (1.75 mL, 15.6 mmol) was addedand the reaction mixture was carefully heated to reflux [Care—vigorousevolution of gas]. The reaction mixture was heated under reflux for 1hour. The suspension was filtered, the filter cake washed with furtherethanol and the filtrate was evaporated under reduced pressure to affordthe title compound (1.66 g, 94%).

LCMS (Method 11); Rt 3.61 min; M+1 569.5.

Also prepared in the same fashion were:

(R)-4-(((tert-Butoxycarbonyl)(2-((tert-butyldimethylsilyl)oxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-3-methoxybenzoicacid

Starting from methyl 4-formyl-3-methoxybenzoate

LCMS Method 11; Rt 3.75 min; ES⁺599.4

(R)-4-(((tert-Butoxycarbonyl)(2-((tert-butyldimethylsilyl)oxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-2-methoxybenzoicacid

Starting from methyl 4-formyl-2-methoxybenzoate

LCMS Method 11; Rt 3.61; ES⁺599.4

(R)-4-(((tert-Butoxycarbonyl)(2-((tert-butyldimethylsilyl)oxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-2-fluorobenzoicacid

Starting from methyl 2-fluoro-4-formylbenzoate

LCMS Method 11; Rt 3.64; ES⁺587.3

(R)-4-(((tert-Butoxycarbonyl)(2-((tert-butyldimethylsilyl)oxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-3-fluorobenzoicacid

Starting from methyl 3-fluoro-4-formylbenzoate

LCMS Method 11; Rt 3.70; ES⁺587.4

(R)-4-(((tert-Butoxycarbonyl)(2-((tert-butyldimethylsilyl)oxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-3-methylbenzoicacid

Starting from methyl 4-formyl-3-methylbenzoate

LCMS Method 11; Rt 3.70; ES⁺587.4

(R)-2-(4-(((tert-Butoxycarbonyl)(2-((tert-butyldimethylsilyl)oxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)phenyl)aceticacid

Starting from methyl 2-(4-formylphenyl)acetate.

LCMS Method 12; Rt 2.93; ES⁺583.4

(R)-4-(((tert-Butoxycarbonyl)(2-((tert-butyldimethylsilyl)oxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-3-(trifluoromethyl)benzoicacid

Starting from methyl 3-trifluoromethyl-4-formylbenzoate

LCMS Method 11; Rt 3.79; ES⁺637.3

Synthesis of methyl 3-trifluoromethyl-4-formylbenzoate

To a solution of 4-methyl-3-trifluoromethylbenzoic acid (1.71 g, 8.37mmol) in DMF (20 mL) was added potassium carbonate (1.39 g, 10.1 mmol)and the reaction mixture was stirred at room temperature for fiveminutes. Iodomethane (0.78 mL, 12.5 mmol) was added and the reactionmixture stirred at room temperature for 18 hours. The reaction mixturewas diluted with ethyl acetate and washed with water and brine (×2).

The organic phase was dried over anhydrous magnesium sulfate, filteredand the filtrate evaporated at reduced pressure to afford methyl4-methyl-3-trifluoromethylbenzoate. The material was dissolved in carbontetrachloride (10 mL) and treated sequentially with N-bromosuccinimide(2.74 g, 15.4 mmol) and benzoyl peroxide (catalytic) and heated at 80°C. for 18 hours. The mixture allowed to cool and diluted with water. Themixture was poured through a hydrophobic fit and the solvent evaporatedat reduced pressure to afford methyl4-(dibromomethyl)-3-trifluoromethylbenzoate. The material was dissolvedin acetone/water (25 mL/5 mL) and silver nitrate (2.38 g, 14.0 mmol)added. The reaction mixture was stirred at room temperature for 72hours. The suspension was filtered through a pad of celite and thefiltrate diluted with ethyl acetate. The solution was washed with waterand brine. The organic phase was dried over anhydrous magnesium sulfate,filtered and evaporated. The residue was dissolved acetone/water (25mL/5 mL) and silver nitrate (2.38 g, 14.0 mmol) added. The reactionmixture was stirred at room temperature for 24 hours. The suspension wasfiltered through a pad of celite and the filtrate diluted with ethylacetate. The solution was washed with water and brine. The organic phasewas dried over anhydrous magnesium sulfate, filtered and evaporated. Theresidue was purified by flash column chromatography (eluent—100%i-hexane to 8:1 i-hexane/ethyl acetate) to afford the title compound(0.537 g, 33%).

¹H NMR (400 MHz, CDCl₃); δ 10.46-10.45 (m, 1H), 8.46 (s, 1H), 8.35 (d,J=8.2 Hz, 1H), 8.20 (d, J=8.2 Hz, 1H), 4.00 (s, 3H).

(R)-4-(((tert-Butoxycarbonyl)(2-((tert-butyldimethylsilyl)oxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-2,3-difluorobenzoicacid

Starting from methyl 2,3-difluoro-4-formylbenzoate (prepared asdescribed for methyl 3-trifluoromethyl-4-formylbenzoate).

LCMS (10 cm_Formic_Aq); Rt 3.66; ES⁺605/607.

(R)-4-(((tert-Butoxycarbonyl)(2-((tert-butyldimethylsilyl)oxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-3-ethoxybenzoicacid

Starting from ethyl 3-ethoxy-4-formylbenzoate.

LCMS Method 11; Rt 3.76; ES⁺613.7.

Synthesis of ethyl 3-ethoxy-4-formylbenzoate

To a solution of 4-formyl-3-hydroxybenzoic acid (1.0 g, 6.02 mmol) inDMF (20 mL) was added potassium carbonate (2.49 g, 18.1 mmol) and ethyliodide (2.82 g, 18.1 mmol). The reaction mixture was stirred at roomtemperature for 72 hours. The reaction mixture was concentrated atreduced pressure and the residue partitioned between ethyl acetate andwater. The organic extract was washed with brine (×2), poured through ahydrophobic frit and the solvent evaporated at reduced pressure. Theresidue was purified by flash column chromatography (eluent—100%i-hexane to 4:1 i-hexane/ethyl acetate) to afford the title compound(1.41 g, 100%).

¹H NMR (400 MHz, CDCl₃); δ 10.55 (s, 1H), 7.87 (d, J=8.3 Hz, 1H), 7.66(d, J=8.3 Hz, 2H), 4.40 (q, J=7.2 Hz, 2H), 4.23 (q, J=7.0 Hz, 2H), 1.51(dd, J=6.9, 6.9 Hz, 3H), 1.41 (dd, J=7.1, 7.1 Hz, 3H).

(R)-4-(((tert-Butoxycarbonyl)(2-((tert-butyldimethylsilyl)oxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-3-isopropoxybenzoicacid

Starting from isopropoxy 3-isopropoxy-4-formylbenzoate (prepared asethyl 3-ethoxy-4-formylbenzoate).

LCMS Method 11; Rt 3.82; ES⁺627.6.

(R)-6-(((tert-Butoxycarbonyl)(2-((tert-butyldimethylsilyl)oxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)nicotinicacid

Starting from methyl 6-formylnicotinate.

LCMS Method 12; Rt 2.83; ES⁺570.4

(R)-4-(((tert-Butoxycarbonyl)(2-((tert-butyldimethylsilyl)oxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-2-fluoro-5-methoxybenzoicacid

Starting from methyl 2-fluoro-4-formyl-5-methoxybenzoate.

LCMS Method 11; Rt 3.66; ES⁺617.6.

Synthesis of methyl 2-fluoro-4-formyl-5-methoxybenzoate

To a solution of methyl 2-fluoro-5-methoxy-4-methylbenzoate (0.576 g,2.91 mmol) in carbon tetrachloride (20 mL) was added N-bromosuccinimide(0.57 g, 3.2 mmol) and benzoyl peroxide (cat). The reaction mixture washeated at 70° C. for 6 hours and then allowed to cool. The suspensionwas filtered and the filtrate evaporated at reduced pressure. Theresidue was dissolved in DCM and washed with water, 1M aqueous sodiumthiosulfate and the organic phase passed through a hydrophobic frit. Thefiltrate was concentrated at reduced pressure and the residue purifiedby flash column chromatography (eluent—100% i-hexane to 4:1i-hexane/ethyl acetate) to afford methyl4-(bromomethyl)-2-fluoro-5-methoxybenzoate (0.591 g, 2.13 mmol). Thismaterial was dissolved in acetonitrile (20 mL) and treated with pyridineN-oxide (0.203 g, 2.13 mmol) and silver (I) oxide (0.247 g, 1.07 mmol)and the mixture stirred at room temperature for 18 hours. The suspensionwas filtered through a pad of celite and the filter pad washed withfurther acetonitrile. The filtrate was evaporated and the residuedissolved in DCM. The DCM solution was washed with water and then passedthrough a hydrophobic fit and the solvent was evaporated. The residuepurified by flash column chromatography (eluent—100% i-hexane to 4:1i-hexane/ethyl acetate) to afford the title compound (0.230 g, 37%).

¹H NMR (400 MHz, CDCl₃); δ 10.45-10.44 (m, 1H), 7.39-7.52 (m, 2H), 3.98(s, 3H), 3.97 (s, 3H).

tert-Butyl(R)-(4-amino-2-methoxybenzyl)(2-((tert-butyldimethylsilyl)oxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)carbamate

From 2-methoxy-4-nitrobenzaldehyde

LCMS Method 11; Rt 3.57 min; ES⁺570.4

tert-Butyl(R)-(4-amino-5-fluoro-2-methoxybenzyl)(2-((tert-butyldimethylsilyl)-oxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)carbamate

From 5-fluoro-2-methoxy-4-nitrobenzaldehyde

LCMS Method 12; Rt 3.60 min; ES+ 588.5

(R)-5-(((tert-Butoxycarbonyl)(2-((tert-butyldimethylsilyl)oxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)picolinicacid

To a solution of tert-butyl(R)-(2-(8-(benzyloxy)-2-oxo-1,2-dihydroquinolin-5-yl)-2-((tert-butyldimethylsilyl)oxy)ethyl)((6-bromopyridin-3-yl)methyl)carbamate(prepared as described in Procedure 4 using 2-bromo-5-formylpyridine inStep 2) (1.47 g, 2.12 mmol) in toluene (50 mL) was added phenyl formate(1.03 g, 8.47 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene(0.294 g, 0.24 mmol), triethylamine (0.59 mL, 4.24 mmol) was added andthe mixture was de-gassed for 15 minutes with nitrogen. Palladiumacetate (0.057 g, 0.25 mmol) was added and the mixture was heated at 80°C. for 18 hours. Further phenyl formate (1.03 g, 8.47 mmol),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.294 g, 0.24 mmol),triethylamine (0.59 mL, 4.24 mmol) and palladium acetate (0.057 g, 0.25mmol) was added and the reaction heated at 80° C. for a further 24hours. The reaction mixture was evaporated at reduced pressure to about⅓ of the initial volume and then diluted with ethyl acetate. The organicphase was washed with water, brine, dried over anhydrous magnesiumsulfate, filtered and the filtrate evaporated at reduced pressure. Theresidue was purified by flash column chromatography (eluent—100%iso-hexane to 100% ethyl acetate) to afford the major component. Thismaterial was dissolved in methanol (20 mL) and 2M aqueous sodiumhydroxide added (2 mL) added. The reaction mixture was stirred at roomtemperature for 18 hours. The reaction mixture was concentrated andwater added. The aqueous was washed with ether and then the aqueous pHadjusted to 5. The aqueous was extracted with DCM (×3), the combined DCMextracts were passed through a hydrophobic frit and evaporated atreduced pressure. The residue was dissolved in ethanol (30 mL) and 10%Pd—C (0.064 g) added followed by 1-methyl-1,4-cyclohexadiene (0.282 g,3.00 mmol). The reaction mixture was heated to reflux and heated atreflux for three hours. The reaction mixture was filtered and thefiltrate evaporated at reduced pressure to afford the title compound(0.314 g, 26%).

LCMS Method 11; Rt 3.37 min; ES⁺570.6

Also prepared by this method:

(R)-4-(((tert-Butoxycarbonyl)(2-((tert-butyldimethylsilyl)oxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-3-(trifluoromethoxy)benzoicacid

Starting from 4-bromo-2-(trifluoromethoxy)benzaldehyde.

LCMS Method 12; Rt 3.02 min; ES⁺653.5.

(R)-4-(((tert-Butoxycarbonyl)(2-((tert-butyldimethylsilyl)oxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-2-fluoro-3-methoxybenzoicacid

Starting from 4-bromo-3-fluoro-2-methoxybenzaldehyde.

LCMS Method 12; Rt 3.02 min; ES⁺ 653.5.

(R)-4-(((tert-Butoxycarbonyl)(2-((tert-butyldimethylsilyl)oxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-3-chlorobenzoicacid

Step 1;(R)-5-(2-Amino-1-((tert-butyldimethylsilyl)oxy)ethyl)-8-hydroxyquinolin-2(1H)-one

To a solution of(R)-5-(2-azido-1-((tert-butyldimethylsilyl)oxy)ethyl)-8-(benzyloxy)quinolin-2(1H)-one(8.5 g, 18.9 mmol) in ethanol (120 mL) was added 10% palladium oncharcoal (8.5 g) followed by 1-methyl-1,4-cyclohexadiene (21 mL, 186.9mmol) and the reaction mixture heated to 60° C. for one hour. Thereaction was allowed to cool to room temperature and the suspension wasfiltered. The filter cake was washed with further ethanol and thefiltrate evaporated at reduced pressure. The residue was triturated withi-hexane, the solid recovered by filtration and subsequently dried undervacuum to afford the title compound (5.55 g, 88%).

¹H NMR (400 MHz, CDCl₃); δ 8.22 (d, J=9.8 Hz, 1H), 7.04 (d, J=8.0 Hz,1H), 6.91 (d, J=7.9 Hz, 1H), 6.63 (d, J=9.3 Hz, 1H), 5.03 (dd, J=4.9,4.9 Hz, 1H), 3.04-2.93 (m, 2H), 0.92-0.85 (m, 9H), 0.20 (s, 3H), −0.18(s, 3H).

Step 2;(R)-4-(((tert-Butoxycarbonyl)(2-((tert-butyldimethylsilyl)oxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-3-chlorobenzoicacid

The title compound was prepared as in Preparation 4 using Step 3 and 5.

LCMS Method 11; Rt 3.76; ES⁺603.3/605.4.

Also prepared in the same fashion were:

(R)-4-(((tert-Butoxycarbonyl)(2-((tert-butyldimethylsilyl)oxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-2-chlorobenzoicacid

Starting from methyl 2-chloro-4-formylbenzoate

LCMS Method 11; Rt 3.70; ES⁺603.3/605.4

(R)-4-(((tert-Butoxycarbonyl)(2-((tert-butyldimethylsilyl)oxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-2-chloro-5-methoxybenzoicacid

Starting from phenyl 2-chloro-4-formyl-5-methoxybenzoate

LCMS Method 11; Rt 3.88; ES⁺633.5/635.6

Synthesis of phenyl 2-chloro-4-formyl-5-methoxybenzoate

To a stirred solution of 4-bromo-2-methoxybenzaldehyde (1.0 g, 4.56 g)in acetonitrile (15 mL) was added N-chlorosuccinimide (0.731 g, 5.48mmol) and the reaction mixture was heated at 80° C. for 18 hours. Thereaction mixture was diluted with ethyl acetate and washed with waterand brine (×2). The organic phase was dried over anhydrous magnesiumsulfate, filtered and the solvent evaporated at reduced pressure. Theresidue was dissolved in toluene (20 mL) and phenyl formate (2 mL, 18.3mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.642 g, 1.11mmol), triethylamine (1.27 mL, 9.13 mmol) was added and the mixture wasde-gassed for 15 minutes with nitrogen. Palladium acetate (0.122 g, 0.54mmol) was added and the mixture was heated at 80° C. for 18 hours. Thereaction mixture was evaporated at reduced pressure to about ⅓ of theinitial volume and then diluted with ethyl acetate. The organic phasewas washed with water, brine, dried over anhydrous magnesium sulfate,filtered and the filtrate evaporated at reduced pressure. The residuewas purified by flash column chromatography (eluent—100% iso-hexane to100% ethyl acetate) to afford the title compound (0.554 g, 42%).

¹H NMR (400 MHz, CDCl₃); δ 10.47 (s, 1H), 7.93 (s, 1H), 7.58 (s, 1H),7.46-7.31 (m, 5H), 4.02 (s, 3H).

Procedure 5. Preparation of(R)-4-(2-((tert-butoxycarbonyl)(2-((tert-butyldimethylsilyl)-oxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzoicacid

Step 1;(R)-8-(Benzyloxy)-5-(1-((tert-butyldimethylsilyl)oxy)-2-((4-hydroxyphenethyl)amino)ethyl)quinolin-2(1H)-one

A mixture of(R)-8-(benzyloxy)-5-(2-bromo-1-((tert-butyldimethylsilyl)-oxy)ethyl)quinolin-2(1H)-one(1.0 g, 2.05 mmol) in NMP (2 mL) was added with tyramine (1.41 g, 10.2mmol). The mixture was heated at 80° C. for 18 hours. The mixture wasdiluted with ethyl acetate and washed sequentially with 10% aqueouspotassium hydrogensulfate and brine (×2). The organic phase was driedover anhydrous magnesium sulfate and the filtrate was evaporated underreduced pressure to afford the title compound (2.58 g, 93%).

¹H NMR (400 MHz, CDCl₃); δ 9.30-9.30 (m, 1H), 8.27 (d, J=9.9 Hz, 1H),7.46-7.38 (m, 6H), 7.08 (d, J=8.3 Hz, 1H), 6.97 (dd, J=4.8, 8.4 Hz, 3H),6.71 (d, J=8.5 Hz, 2H), 6.65 (d, J=9.9 Hz, 1H), 5.16 (s, 2H), 5.14-5.07(m, 1H), 2.97-2.82 (m, 3H), 2.78-2.68 (m, 3H), 1.65 (br s, 1H), 0.82 (s,9H), 0.00 (s, 3H), −0.22 (s, 3H).

Step 2; (R)-tert-Butyl(2-(8-(benzyloxy)-2-oxo-1,2-dihydroquinolin-5-yl)-2-((tert-butyldimethylsilyl)oxy)ethyl)(4-hydroxyphenethyl)carbamate

To a stirred solution of(R)-8-(benzyloxy)-5-(1-((tert-butyldimethylsilyl)oxy)-2-((4-hydroxyphenethyl)amino)ethyl)quinolin-2(1H)-one(6.0 g, 11.02 mmol) in DCM (75 mL) was added a solution ofdi-tert-butyldicarbonate (2.18 g, 16.5 mmol) in DCM (15 mL). Thereaction mixture was stirred at room temperature for 2 hours. Thesolvent was evaporated under reduced pressure and the residue purifiedby flash column chromatography (eluent—100% iso-hexane to 3:2iso-hexane/ethyl acetate) to afford the title compound (6.30 g, 89%).

¹H NMR (400 MHz, DMSO-d₆, 100° C.); δ 9.94-9.92 (m, 1H), 8.74 (s, 1H),8.29 (d, J=9.9 Hz, 1H), 7.56 (d, J=7.2 Hz, 2H), 7.44-7.35 (m, 3H), 7.24(d, J=8.3 Hz, 1H), 7.14 (d, J=8.4 Hz, 1H), 6.92 (d, J=8.4 Hz, 2H),6.70-6.67 (m, 2H), 6.56 (d, J=9.9 Hz, 1H), 5.31 (s, 3H), 3.37-3.23 (m,4H), 2.66-2.55 (m, 2H), 1.39 (s, 9H), 0.86 (s, 9H), 0.04 (s, 3H), −0.13(s, 3H).

Step 3;(R)-4-(2-((2-(8-(Benzyloxy)-2-oxo-1,2-dihydroquinolin-5-yl)-2-((tert-butyldimethylsilyl)oxy)ethyl)(tert-butoxycarbonyl)amino)ethyl)phenyltrifluoromethanesulfonate

To a cooled solution of (R)-tert-butyl(2-(8-(benzyloxy)-2-oxo-1,2-dihydroquinolin-5-yl)-2-((tert-butyldimethylsilyl)oxy)ethyl)(4-hydroxyphenethyl)-carbamate(6.3 g, 9.78 mmol) in DCM (100 mL) at 0° C. was added triethylamine(2.72 mL, 19.56 mmol) followed by2-[N,N-bis(trifluoromethanesulfonyl)amino]-5-chloropyridine (4.21 g,10.76 mmol) and the mixture was stirred at 0° C. for 2 hours. Thecoolant was removed and 2M aqueous sodium hydroxide (25 mL) was added tothe reaction mixture, and the mixture was stirred for 15 minutes. Theorganic phase was separated, dried over anhydrous magnesium sulfate,filtered and the filtrate evaporated under reduced pressure to affordthe title compound (7.3 g, 96%).

¹H NMR (400 MHz, DMSO-d₆, 100° C.); δ 8.74 (s, 1H), 8.29 (d, J=9.9 Hz,1H), 7.56 (d, J=7.2 Hz, 2H), 7.44-7.35 (m, 3H), 7.24 (d, J=8.3 Hz, 1H),7.14 (d, J=8.4 Hz, 1H), 6.92 (d, J=8.4 Hz, 2H), 6.70-6.67 (m, 2H), 6.56(d, J=9.9 Hz, 1H), 5.31 (s, 3H), 2.96 (s, 4H), 2.66-2.55 (m, 2H), 1.39(s, 9H), 0.86 (s, 9H), 0.04 (s, 3H), −0.13 (s, 3H).

Step 4; (R)-Phenyl4-(2-((2-(8-(benzyloxy)-2-oxo-1,2-dihydroquinolin-5-yl)-2-((tert-butyldimethylsilyl)oxy)ethyl)(tert-butoxycarbonyl)amino)ethyl)benzoate

To a solution of(R)-4-(2-((2-(8-(benzyloxy)-2-oxo-1,2-dihydroquinolin-5-yl)-2-((tert-butyldimethylsilyl)oxy)ethyl)(tert-butoxycarbonyl)amino)ethyl)phenyltrifluoromethanesulfonate (7.29 g, 9.4 mmol) in toluene (75 mL) wasadded phenyl formate (4 mL, 37.57 mmol),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (1.3 g, 2.25 mmol),triethylamine (2.61 mL, 18.81 mmol) and the mixture was de-gassed for 15minutes with nitrogen. Palladium acetate (0.242 g, 1.12 mmol) was addedand the mixture was heated at 80° C. for 6 hours. The reaction mixturewas evaporated under reduced pressure to about ⅓ of the initial volumeand then diluted with ethyl acetate. The organic phase was washed withwater, brine, dried over anhydrous magnesium sulfate, filtered and thefiltrate evaporated under reduced pressure. The residue was purified byflash column chromatography (eluent—100% iso-hexane to 100% ethylacetate) to afford the title compound (4.5 g, 64%).

¹H NMR (400 MHz, DMSO-d₆, 100° C.); δ 9.98-9.96 (m, 1H), 8.29 (d, J=9.9Hz, 1H), 8.05 (d, J=8.3 Hz, 2H), 7.56 (d, J=7.2 Hz, 2H), 7.51-7.46 (m,2H), 7.43-7.27 (m, 8H), 7.24 (s, 1H), 7.17 (d, J=8.3 Hz, 1H), 6.57 (d,J=9.9 Hz, 1H), 5.35 (d, J=1.9 Hz, 1H), 5.32 (s, 2H), 3.49-3.34 (m, 4H),2.90-2.80 (m, 2H), 1.39 (s, 9H), 0.87 (s, 9H), 0.06 (s, 3H), −0.12 (s,3H).

Step 5;(R)-4-(2-((2-(8-(Benzyloxy)-2-oxo-1,2-dihydroquinolin-5-yl)-2-((tert-butyldimethylsilyl)oxy)ethyl)(tert-butoxycarbonyl)amino)ethyl)benzoicacid

To a solution of (R)-phenyl4-(2-((2-(8-(benzyloxy)-2-oxo-1,2-dihydroquinolin-5-yl)-2-((tert-butyldimethylsilyl)oxy)ethyl)(tert-butoxycarbonyl)amino)ethyl)benzoate(4.5 g, 6.0 mmol) in THF (30 mL) was added 2M aqueous sodium hydroxide(30 mL) and the mixture was stirred at room temperature for 16 hours.The solvent was evaporated under reduced pressure to half the initialvolume and then diluted with water (25 mL), The resulting mixture wasacidified to pH 3 using 2M aqueous hydrochloric acid and then extractedwith ethyl acetate (×3). The combined organic phases were washedsequentially with water, brine (25 ml), dried over anhydrous magnesiumsulfate, filtered and the filtrate evaporated under reduced pressure toafford the title compound (4 g, 100%). Material used directly in thenext step.

Step 6;(R)-4-(2-((tert-Butoxycarbonyl)(2-((tert-butyldimethylsilyl)oxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzoicacid

To a solution of(R)-4-(2-((2-(8-(benzyloxy)-2-oxo-1,2-dihydroquinolin-5-yl)-2-((tert-butyldimethylsilyl)oxy)ethyl)(tert-butoxycarbonyl)amino)ethyl)benzoicacid (4 g, 5.95 mmol) in ethanol (100 mL) was added 10% Pd—C (2 g) and1-methyl-1,4-cyclohexadiene (3.29 ml, 29.76 mmol) and the mixture washeated at 80° C. for 3.5 hours. The reaction mixture was filteredthrough celite and the celite washed with further ethanol. The filtratewas evaporated under reduced pressure to afford the title compound (3.5g, 100%).

Procedure 6. Preparation of (R)-tert-butyl(2-((tert-butyldimethylsilyl)oxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)(piperidin-4-ylmethyl)carbamate

Step 1;(R)-8-(Benzyloxy)-5-(2-(((1-benzylpiperidin-4-yl)methyl)amino)-1-((tert-butyldimethylsilyl)oxy)ethyl)quinolin-2(1H)-one

To a mixture of(R)-8-(benzyloxy)-5-(2-bromo-1-((tert-butyldimethylsilyl)-oxy)ethyl)quinolin-2(1H)-one(2.39 g, 4.90 mmol) in NMP (4 mL) was added(1-benzylpiperidin-4-yl)methanamine (5 g, 24.5 mmol). The mixture washeated at 80° C. for 18 hours. The mixture was diluted with ethylacetate and washed sequentially with water (×2) and brine (×2). Theorganic phase was dried over anhydrous magnesium sulfate and thefiltrate was evaporated. The residue was purified by flash columnchromatography (eluent—100% DCM to 40:1 DCM/7M NH₃/MeOH) to afford thetitle compound (2.65 g, 88%).

¹H NMR (400 MHz, CDCl₃); δ 9.19-9.15 (m, 1H), 8.30-8.28 (s, 1H),7.43-7.41 (m, 5H), 7.31 (d, J=4.4 Hz, 5H), 7.12 (d, J=8.3 Hz, 1H), 7.00(d, J=8.3 Hz, 1H), 6.66 (d, J=9.9 Hz, 1H); 5.16 (s, 2H), 5.15-5.10 (m,1H), 3.49 (s, 2H), 2.95-2.84 (m, 3H), 2.71 (dd, J=4.0, 12.2 Hz, 1H),2.56-2.43 (m, 2H), 1.94 (dd, J=11.7, 11.7 Hz, 2H), 1.51-1.39 (m, 2H),1.30-1.22 (m, 3H), 0.87 (s, 9H), 0.06 (s, 3H), −0.19 (s, 3H).

Step 2; (R)-tert-Butyl(2-(8-(benzyloxy)-2-oxo-1,2-dihydroquinolin-5-yl)-2-((tert-butyldimethylsilyl)oxy)ethyl)((1-benzylpiperidin-4-yl)methyl)carbamate

To a stirred solution of(R)-8-(benzyloxy)-5-(2-(((1-benzylpiperidin-4-yl)methyl)amino)-1-((tert-butyldimethylsilyl)oxy)ethyl)quinolin-2(1H)-one(2.65 g, 4.33 mmol) in DCM (25 mL) was added a solution ofdi-tert-butyldicarbonate (1.13 g, 5.18 mmol) in DCM (5 mL). The reactionmixture was stirred at room temperature for 16 hours. The solvent wasevaporated under reduced pressure and the residue purified by flashcolumn chromatography (eluent—100% DCM to 30:1 DCM/7M NH₃/MeOH) toafford the title compound (2.83 g, 92%).

¹H NMR (400 MHz, DMSO-d₆, 100° C.); δ 9.96 (s, 1H), 8.30 (d, J=9.9 Hz,1H), 7.55 (d, J=7.3 Hz, 2H), 7.42-7.21 (m, 9H), 7.14 (d, J=8.3 Hz, 1H),6.55 (d, J=9.9 Hz, 1H), 5.40-5.33 (m, 1H), 5.30 (s, 2H), 3.44 (s, 2H),3.38 (d, J=6.1 Hz, 2H), 3.12-2.97 (m, 2H), 2.95 (s, 2H), 2.78-2.73 (m,2H), 2.00-1.88 (m, 2H), 1.40 (s, 10H), 1.22-1.09 (m, 2H), 0.87 (s, 9H),0.06 (s, 3H), −0.13 (s, 3H).

Step 3; (R)-tert-Butyl(2-((tert-butyldimethylsilyl)oxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)(piperidin-4-ylmethyl)carbamate

To a stirred solution of (R)-tert-butyl(2-(8-(benzyloxy)-2-oxo-1,2-dihydroquinolin-5-yl)-2-((tert-butyldimethylsilyl)oxy)ethyl)((1-benzylpiperidin-4-yl)methyl)carbamate(2.80 g, 4.33 mmol) in ethanol (30 mL) was added 10% Pd/C (2.8 g) and1-methyl-1,4-cyclohexadiene (4.86 mL, 43.3 mmol). The reaction mixturewas heated to reflux [care—vigorous evolution of gas] and heated underreflux for 1 hour. The suspension was filtered and the filtrateevaporated under reduced pressure to afford the title compound (2.26 g,98%).

¹H NMR (400 MHz, DMSO-d₆, 100° C.); δ 8.26 (d, J=9.9 Hz, 1H), 7.05 (d,J=8.2 Hz, 1H), 7.01 (d, J=8.0 Hz, 1H), 6.53-6.49 (m, 1H), 5.37-5.35 (m,1H), 3.22 (d, J=12.8 Hz, 2H), 3.08 (ddd, J=7.0, 14.3, 17.8 Hz, 2H),2.83-2.72 (m, 2H), 1.84-1.76 (m, 1H), 1.71-1.61 (m, 2H), 1.43-1.41 (m,14H), 0.87-0.85 (m, 9H), 0.02 (s, 3H), −0.14 (d, J=2.1 Hz, 3H).

Also Prepared by this Method (R)-tert-butyl(2-((tert-butyldimethylsilyl)oxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)(2-(piperidin-4-yl)ethyl)carbamate

¹H NMR (400 MHz, DMSO-d₆, 90° C.); δ 8.26 (d, J=9.9 Hz, 1H), 7.05 (d,J=8.2 Hz, 1H), 7.01 (d, J=8.0 Hz, 1H), 6.53-6.49 (m, 1H), 5.37-5.35 (m,1H), 3.40-3.30 (m, 2H), 3.25-3.10 (m, 2H), 3.00-2.90 (m, 2H), 2.50-2.40(m, 2H), 1.60-1.55 (m, 2H), 1.45 (s, 9H), 1.40-1.30 (m, 2H), 1.20-0.95(m, 3H), 0.87-0.85 (m, 9H), 0.02 (s, 3H), −0.14 (d, J=2.1 Hz, 3H).

Procedure 7. Preparation of(S)-4-((3-(2-((1-benzylpiperidin-4-yl)methoxy)-1-hydroxy-2-oxo-1-phenylethyl)phenoxy)methyl)benzoicacid hydrochloride

Step 1; (S)-tert-Butyl4-((2-hydroxy-2-(3-hydroxyphenyl)-2-phenylacetoxy)methyl-)piperidine-1-carboxylate

To a stirred solution of(S)-2-hydroxy-2-(3-hydroxyphenyl)-2-phenylacetic acid (10.69 g, 43.77mmol) in DMF (30 mL) was added potassium hydrogen carbonate (8.76 g,87.5 mmol) and the mixture stirred at room temperature for 10 minutes. Asolution of tert-butyl 4-(tosyloxymethyl)piperidine-1-carboxylate (asdescribed in Example 1, Step 5) (16.17 g, 43.77 mmol) in DMF (55 mL) wasadded and the reaction mixture heated at 60° C. for 27 hours. Dilutedwith ethyl acetate and washed with aqueous sodium hydrogen carbonate(×2), brine and dried over anhydrous magnesium sulfate. The filtrate wasevaporated under reduced pressure and the residue purified by flashcolumn chromatography (eluent—100% iso-hexane to 2:3 iso-hexane/ethylacetate) to afford the title compound (13.42 g, 69%).

¹H NMR (400 MHz, DMSO-d₆); δ 9.35 (s, 1H), 7.33 (d, J=4.4 Hz, 4H),7.31-7.26 (m, 1H), 7.12 (dd, J=7.8, 7.8 Hz, 1H), 6.77-6.73 (m, 2H),6.69-6.66 (m, 1H), 6.50 (s, 1H), 4.07-3.99 (m, 2H), 3.87 (d, J=11.4 Hz,2H), 2.68-2.63 (m, 2H), 1.76-1.67 (m, 1H), 1.48 (d, J=12.0 Hz, 2H), 1.38(s, 9H), 1.10-0.83 (m, 2H).

Step 2; (S)-Piperidin-4-ylmethyl2-hydroxy-2-(3-hydroxyphenyl)-2-phenylacetate hydrochloride

To a solution of (S)-tert-butyl4-((2-hydroxy-2-(3-hydroxyphenyl)-2-phenylacetoxy)methyl)piperidine-1-carboxylate(7.07 g, 16.01 mmol) in 1,4-dioxane (20 mL) was added a solution ofHCl-dioxane (4M, 80 mL) and the reaction mixture was stirred at roomtemperature for 1 hour 30 minutes. The solvent was evaporated underreduced pressure to afford the title compound (5.9 g, 97%).

¹H NMR (400 MHz, DMSO-d₆); δ 9.38 (s, 1H), 8.69-8.68 (m, 1H), 8.39 (s,1H), 7.34 (d, J=4.0 Hz, 4H), 7.32-7.27 (m, 1H), 7.13 (dd, J=7, 8, 7.8Hz, 1H), 6.78-6.74 (m, 2H), 6.70-6.67 (m, 1H), 6.52 (s, 1H), 4.02 (d,J=6.5 Hz, 2H), 3.21 (d, J=12.4 Hz, 2H), 2.86-2.77 (m, 2H), 1.92-1.84 (m,1H), 1.68 (d, J=13.9 Hz, 2H), 1.35-1.25 (m, 2H).

Step 3; (S)-(1-Benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-hydroxyphenyl)-2-phenylacetate

To a stirred suspension of (S)-piperidin-4-ylmethyl2-hydroxy-2-(3-hydroxyphenyl)-2-phenylacetate hydrochloride (5.9 g,15.61 mmol) in DCM (160 mL) was added benzaldehyde (2.38 mL, 23.4 mmol)and stirred at 30° C. for 1 hour. Sodium triacetoxyborohydride (6.62 g,31.2 mmol) was added and the reaction mixture stirred at 30° C. for 2hours. Further sodium triacetoxyborohydride (1.65 g, 7.8 mmol) was addedand the mixture stirred at 30° C. for 18 hours. The reaction mixture wasquenched with saturated aqueous sodium hydrogen carbonate and theorganic phase removed. The aqueous phase was extracted with further DCM.The combined organic phases were washed with brine, dried over anhydrousmagnesium sulfate, filtered and the filtrate evaporated under reducedpressure. The residue was purified by flash column chromatography(eluent—100% DCM to 9:1 DCM/methanol) to afford the title compound(13.42 g, 69%).

¹H NMR (400 MHz, DMSO-d₆); δ 9.33 (s, 1H), 7.34-7.25 (m, 9H), 7.11 (dd,J=7.8, 7.8 Hz, 1H), 6.76-6.73 (m, 2H), 6.68-6.65 (m, 1H), 6.48 (s, 1H),5.77 (s, 1H), 3.99 (d, J=6.3 Hz, 2H), 3.40 (s, 2H), 2.72 (d, J=11.4 Hz,2H), 1.86-1.79 (m, 2H), 1.54-1.43 (m, 3H), 1.12 (q, J=11.8 Hz, 2H).

Step 4; (S)-tert-Butyl4-((3-(2-((1-benzylpiperidin-4-yl)methoxy)-1-hydroxy-2-oxo-1-phenylethyl)phenoxy)methyl)benzoate

To a stirred solution of (S)-(1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-hydroxyphenyl)-2-phenylacetate (1.23 g, 2.84 mmol) in DMF(15 mL) was added potassium carbonate (0.785 g, 5.69 mmol) and themixture stirred at room temperature for 5 minutes. tert-Butyl4-(bromomethyl)benzoate (0.924 g, 6.83 mmol) was added and the reactionmixture was heated at 40° C. for 8 hours. Diluted with ethyl acetate andwashed with aqueous sodium hydrogen carbonate (×2), brine and dried overanhydrous magnesium sulfate. The filtrate was evaporated under reducedpressure and the residue purified by flash column chromatography(eluent—100% DCM to 7:3 DCM/methanol) to afford the title compound (1.89g, 100%).

¹H NMR (400 MHz, DMSO-d₆); δ 7.89 (d, J=8.4 Hz, 2H), 7.50 (d, J=8.4 Hz,2H), 7.30-7.23 (m, 11H), 6.97-6.91 (m, 3H), 6.60 (s, 1H), 5.15 (s, 2H),3.98 (d, J=6.3 Hz, 2H), 3.39 (s, 2H), 2.74-2.68 (m, 2H), 1.85-1.77 (m,2H), 1.55 (s, 9H), 1.53-1.43 (m, 3H), 1.18-1.06 (m, 2H).

Step 5;(S)-4-((3-(2-((1-Benzylpiperidin-4-yl)methoxy)-1-hydroxy-2-oxo-1-phenylethyl)phenoxy)methyl)benzoicacid hydrochloride

To a stirred solution of (S)-tert-butyl4-((3-(2-((1-benzylpiperidin-4-yl)methoxy)-1-hydroxy-2-oxo-1-phenylethyl)phenoxy)methyl)benzoate(1.89 g, 3.04 mmol) in 1,4-dioxane (5 mL) was added a solution ofHCl-dioxane (4M, 15 mL) and the reaction mixture stirred at roomtemperature for 18 hours. The solvent was evaporated under reducedpressure to afford the title compound (1.83 g, 100%).

¹H NMR (400 MHz, DMSO-d₆); δ 7.95 (d, J=8.3 Hz, 2H), 7.52 (d, J=8.3 Hz,4H), 7.48-7.44 (m, 3H), 7.32 (dd, J=3.4, 3.4 Hz, 6H), 6.99-6.90 (m, 3H),6.64 (s, 1H), 5.15 (s, 2H), 4.24-4.19 (m, 2H), 4.00 (d, J=6.4 Hz, 2H),3.28 (s, 1H), 3.06 (s, 1H), 2.90-2.88 (m, 2H), 1.82 (s, 1H), 1.71 (d,J=13.2 Hz, 2H), 1.44 (d, J=11.7 Hz, 2H).

Procedure 8. Preparation of(S)-3-((3-(2-((1-benzylpiperidin-4-yl)methoxy)-1-hydroxy-2-oxo-1-phenylethyl)phenoxy)methyl)benzoicacid hydrochloride

The title compound was prepared as in Procedure 7 with tert-butyl3-(bromomethyl)benzoate replacing tert-butyl 4-(bromomethyl)benzoate inStep 4.

Procedure 9. Preparation of(S)-2-(3-(2-((1-benzylpiperidin-4-yl)methoxy)-1-hydroxy-2-oxo-1-phenylethyl)phenoxy)aceticacid hydrochloride

The title compound was prepared as in Procedure 7 with tert-butylbromoacetate replacing tert-butyl 4-(bromomethyl)benzoate in Step 4.

Procedure 10. Preparation of (S)-(1-benzylpiperidin-4-yl)methyl2-hydroxy-2-phenyl-2-(3-(piperidin-4-ylmethoxy)phenyl)acetatehydrochloride

The title compound was prepared as in Procedure 7 with tert-butyl4-(tosyloxymethyl)piperidine-1-carboxylate (as described in Example 1,Step 5) replacing tert-butyl 4-(bromomethyl)benzoate in Step 4.

Procedure 6. Preparation of (S)-(1-benzylpiperidin-4-yl)methyl2-(3-(azetidin-3-ylmethoxy)phenyl)-2-hydroxy-2-phenylacetate2,2,2-trifluoroacetate

Step 1; (S)-tert-Butyl3-((3-(2-((1-benzylpiperidin-4-yl)methoxy)-1-hydroxy-2-oxo-1-phenylethyl)phenoxy)methyl)azetidine-1-carboxylate

The title compound was prepared as in Procedure 7 with tert-butyl3-(bromomethyl)azetidine-1-carboxylate replacing tert-butyl4-(bromomethyl)benzoate in Step 4.

¹H NMR (400 MHz, DMSO-d₆); δ 7.35-7.21 (6H), 6.89 (dd, J=6.3, 6.3 Hz,3H), 6.60 (s, 1H), 4.06-3.89 (m, 6H), 3.82 (d, J=6.8 Hz, 2H), 3.71 (d,J=7.2 Hz, 2H), 3.65-3.54 (m, 4H), 3.40 (s, 2H), 2.95-2.86 (m, 1H), 2.71(d, J=11.8 Hz, 2H), 1.83 (dd, J=11.4, 11.4 Hz, 2H), 1.53-1.43 (m, 2H),1.38 (s, 9H), 1.22-1.08 (m, 2H).

Step 2; (S)-(1-Benzylpiperidin-4-yl)methyl2-(3-(azetidin-3-ylmethoxy)phenyl)-2-hydroxy-2-phenylacetate2,2,2-trifluoroacetate

To a solution of (S)-tert-butyl3-(3-(2-((1-benzylpiperidin-4-yl)methoxy)-1-hydroxy-2-oxo-1-phenylethyl)phenoxy)methyl)azetidine-1-carboxylate(0.388 g, 0.65 mmol) in DCM (2 mL) was added trifluoroacetic acid (2mL). The reaction mixture was stirred at room temperature for 1 hour.The solvent was evaporated under reduced pressure and the title compoundwas used without further purification in subsequent steps.

Procedure 12. Preparation of (S)-(1-benzylpiperidin-4-yl)methyl2-(3-(3-aminopropoxy)phenyl)-2-hydroxy-2-phenylacetate hydrochloride

The title compound was prepared as in Procedure 7 with tert-butyl(3-bromopropyl)carbamate replacing tert-butyl 4-(bromomethyl)benzoate inStep 4.

Procedure 13. Preparation of (R)-(1-benzylpiperidin-4-yl)methyl2-(3-(3-aminoethoxy)phenyl)-2-hydroxy-2-phenylacetate hydrochloride

The title compound was prepared as in Procedure 7 with(R)-2-hydroxy-2-(3-hydroxyphenyl)-2-phenylacetic acid replacing(S)-2-hydroxy-2-(3-hydroxyphenyl)-2-phenylacetic acid in Step 1 andtert-butyl (2-chloroethyl)carbamate replacing tert-butyl4-(bromomethyl)benzoate in Step 4.

Procedure 14, Preparation of (1-benzylpiperidin-4-yl)methyl2-(3-(2-aminoethyl)phenyl)-2-hydroxy-2-phenylacetate

Step 1; tert-Butyl4-((2-hydroxy-2-(3-hydroxyphenyl)-2-phenylacetoxy)methyl)-piperidine-1-carboxylate

To a stirred solution of tert-butyl4-((2-(3-(benzyloxy)phenyl)-2-hydroxy-2-phenylacetoxy)methyl)piperidine-1-carboxylate(18.4 g, 34.6 mmol) in ethanol (300 mL) was added 10% Pd/C (4.6 g) and1-methyl-1,4-cyclohexadiene (19.6 mL, 173.2 mmol). The reaction mixturewas heated to reflux for two hours. The suspension was filtered throughcelite and the filtrate evaporated under reduced pressure to afford thetitle product (15.5 g, 100%).

¹H NMR (400 MHz, CDCl₃); δ 7.41-7.30 (m, 6H), 7.20 (dd, J=8.0, 8.0 Hz,1H), 7.00 (s, 1H), 6.87 (s, 1H), 6.80 (dd, J=2.1, 8.0 Hz, 1H), 4.22 (s,1H), 4.10 (d, J=5.9 Hz, 2H), 4.08-4.02 (m, 2H), 3.75-3.69 (m, 1H),2.68-2.57 (m, 2H), 1.83-1.74 (m, 1H), 1.69-1.55 (m, 1H), 1.49 (d, J=12.7Hz, 1H), 1.40 (s, 9H), 1.21-1.04 (m, 1H).

Step 2; tert-Butyl4-((2-hydroxy-2-phenyl-2-(3-(((trifluoromethyl)sulfonyl)oxy)-phenyl)acetoxy)methyl)piperidine-1-carboxylate

The title compound was prepared as described in Procedure 5 Step 3 withtert-butyl4-((2-hydroxy-2-(3-hydroxyphenyl)-2-phenylacetoxy)methyl)piperidine-1-carboxylatereplacing (R)-tert-Butyl(2-(8-(benzyloxy)-2-oxo-1,2-dihydroquinolin-5-yl)-2-((tert-butyldimethylsilyl)oxy)ethyl)(4-hydroxyphenethyl)carbamate.The product was used directly in the next step.

Step 3; Piperidin-4-ylmethyl2-hydroxy-2-phenyl-2-(3-(((trifluoromethyl)sulfonyl)-oxy)phenyl)acetatehydrochloride

The title compound was prepared as described in Procedure 7 Step 2.

¹H NMR (400 MHz, DMSO-d₆); δ 7.57 (dd, J=8.0, 8.0 Hz, 1H), 7.49-7.46 (m,2H), 7.41-7.31 (m, 6H), 7.05 (s, 1H), 4.06 (d, J=6.7 Hz, 2H), 3.21 (d,J=12.4 Hz, 2H), 2.85-2.75 (m, 2H), 1.93-1.85 (m, 1H), 1.69-1.60 (m, 2H),1.36-1.25 (m, 2H).

Step 4; (1-Benzylpiperidin-4-yl)methyl2-hydroxy-2-phenyl-2-(3-(((trifluoromethyl)sulfonyl)oxy)phenyl)acetate

The title compound was prepared as described in Procedure 7 Step 3.

¹H NMR (400 MHz, CDCl₃); δ 7.52 (d, J=7.9 Hz, 1H), 7.44-7.39 (m, 2H),7.37-7.21 (m, 11H), 4.33 (s, 1H), 4.12 (d, J=6.8 Hz, 2H), 3.49 (s, 2H),3.46 (s, 2H), 2.82 (d, J=11.5 Hz, 2H), 1.92-1.84 (m, 2H), 1.52-1.44 (m,1H), 1.27-1.15 (m, 2H).

Step 5; (1-Benzylpiperidin-4-yl)methyl2-(3-(2-((tert-butoxycarbonyl)amino)-ethyl)phenyl)-2-hydroxy-2-phenylacetate

A mixture of (1-benzylpiperidin-4-yl)methyl2-hydroxy-2-phenyl-2-(3-(((trifluoromethyl)sulfonyl)oxy)phenyl)acetate(1.56 g, 2.77 mmol), potassium tert-butylN-[2-(trifluoroboranuidyl)ethyl]carbamate (0.7 g, 2.79 mmol), palladium(II) acetate (0.09 g, 0.41 mmol), RuPhos (0.39 g, 0.83 mmol) and cesiumcarbonate (2.92 g, 8.3 mmol) in toluene/water (30 mL, 3 to 1) wasthoroughly degassed with nitrogen and then heated at 95° C. for 16hours. The reaction mixture was partitioned between DCM and brine. Theorganic phase passed through a hydrophobic frit and the filtrateevaporated under reduced pressure. The residue purified by flash columnchromatography (eluent—100% hexane to 100% ethyl acetate) to afford thetitle compound (1.21 g, 78%).

Step 6: (1-Benzylpiperidin-4-yl)methyl2-(3-(2-aminoethyl)phenyl)-2-hydroxy-2-phenylacetate hydrochloride

The title compound was prepared as in Procedure 7 Step 2.

Procedure 15. Preparation of1-Benzylpiperidin-4-yl(S)-2-(3-((4-(aminomethyl)benzyl)oxy)phenyl)-2-hydroxy-2-phenylacetatedihydrochloride

The title compound was prepared as in Procedure 6 with tert-butyl(4-(bromomethyl)benzyl)carbamate replacing tert-butyl4-(bromomethyl)benzoate in Step 4.

Example 5. (S)-(1-Benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-((1-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzoyl)piperidin-4-yl)methoxy)phenyl)-2-phenylacetate(Compound 31)

To a stirred solution of(R)-4-(2-((tert-butoxycarbonyl)(2-((tert-butyldimethylsilyl)oxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzoicacid (0.13 g, 0.23 mmol) and N,N-diisopropylethylamine (0.066 mL, 0.38mmol) in DMF (2 mL) was added HATU (0.11 g, 0.29 mmol) and the mixturestirred at room temperature for 30 minutes, A solution of(S)-(1-benzylpiperidin-4-yl)methyl2-hydroxy-2-phenyl-2-(3-(piperidin-4-ylmethoxy)phenyl)acetatehydrochloride (0.11 g, 0.19 mmol) in DMF (1 mL) was added and thereaction mixture stirred at room temperature for 18 hours. The reactionmixture was diluted with ethyl acetate and washed with water and brine(×2). The organic phase was dried over anhydrous magnesium sulfate andthe filtrate was evaporated under reduced pressure. The residue wastreated with a solution of HCl-dioxane (4M, 15 mL) and the reactionmixture stirred at room temperature for 18 hours. The solvent wasevaporated under reduced pressure and the residue purified by reversephase preparative HPLC, to afford the title compound (31).

The following compounds were prepared as described in Example 4 with therelevant acid coupled to the appropriate amine.

N Relevant acid Relevant Amine Structure 32

32A

32B

32C

32D

32E

32F

32G

32H

32I

32J

32K

32L

32M

33

33A

34

35

36

36A

37

38

39

40

41

42

42A

42B

42C

42D

42E

42F

Salt (2 eq N Rt (min) Method NMR data (400 MHz) unless stated) 31 7.32 7(DMSO-d₆, 90° C.); δ 8.25 (s, 1H), 8.18 (d, J = 9.9 Hz, 1H), 7.33-7.22(m, mono Formate 15H), 7.08 (d, J = 8.2 Hz, 1H), 6.93 (d, J = 8.0 Hz,1H), 6.89-6.86 (m, 3H), 6.52 (d, J = 9.9 Hz, 1H), 5.13-5.08 (m, 1H),4.55-4.42 (m, 1H), 4.02-3.99 (m, 2H), 3.79 (d, J = 6.1 Hz, 2H),3.67-3.55 (m, 1H), 3.39 (s, 2H), 2.95-2.85 (m, 4H), 2.84-2.76 (m, 3H),2.75-2.67 (m, 2H), 2.04-1.95 (m, 1H), 1.87-1.67 (m, 4H), 1.53-1.42 (m,3H), 1.24-1.07 (m, 4H). 32 7.18 7 (MeOD); δ 8.50 (s, 2H), 8.29 (d, J =9.9 Hz, 1H), 7.87 (d, J = 8.4 Hz, 2H), Formate 7.56 (d, J = 8.4 Hz, 2H),7.40 (s, 6H), 7.39-7.32 (m, 4H), 7.28-7.23 (m, 2H), 7.03-6.96 (m, 3H),6.90 (dd, J = 2.4, 8.2 Hz, 1H), 6.64 (d, J = 9.8 Hz, 1H), 5.36 (dd, J =4.4, 8.8 Hz, 1H), 4.21 (s, 2H), 4.11-4.03 (m, 4H), 3.94 (s, 2H), 3.57(dd, J = 6.9, 6.9 Hz, 2H), 3.22-3.09 (m, 4H), 2.55 (dd, J = 10.4, 12.3Hz, 2H), 2.05 (s, 3H), 1.84-1.78 (m, 1H), 1.70 (d, J = 12.9 Hz, 2H),1.36 (q, J = 12.5 Hz, 2H). 32A 2.47 11 (MeOD); δ 8.47 (s, 2H), 8.26 (d,J = 9.9 Hz, 1H), 7.54 (s, 1H), 7.51-7.25 (m, Formate 14H), 7.04 (d, J =8.2 Hz, 1H), 7.00-6.96 (m, 2H), 6.91 (dd, J = 2.2, 8.0 Hz, 1H), 6.65 (d,J = 9.8 Hz, 1H), 5.46-5.38 (m, 1H), 4.34 (s, 2H), 4.13-4.04 (m, 6H),3.97 (s, 3H), 3.59 (dd, J = 6.9, 6.9 Hz, 2H), 3.29 (d, J = 12.7 Hz, 2H),3.22-3.18 (m, 2H), 177-2.67 (m, 2H), 2.15-2.07 (m, 2H), 1.93-1.82 (m,1H), 1.74 (d, J = 13.6 Hz, 2H), 1.48-1.37 (m, 2H). 32B 2.51 11 (MeOD); δ8.53 (s, 1H), 8.30 (d, J = 9.9 Hz, 1H), 7.90 (d, J = 7.9 Hz, 1H),mono-formate 7.41-7.23 (m, 13H), 7.14 (dd, J = 1.2, 7.9 Hz, 1H),7.04-6.98 (m, 3H), 6.93 (dd, J = 2.0, 8.2 Hz, 1H), 6.64 (d, J = 9.9 Hz,1H), 5.37 (dd, J = 4.8, 8.3 Hz, 1H), 4.17 (s, 2H), 4.11-4.05 (m, 4H),3.93 (s, 2H), 3.89 (s, 3H), 3.60 (t, J = 6.7 Hz, 2H), 3.20-3.09 (m, 4H),2.53 (dd, J = 10.2, 12.2 Hz, 2H), 2.13-2.06 (m, 2H), 1.86-1.73 (m, 1H),1.71-1.63 (m, 2H), 1.42-1.29 (m, 2H). 32C 2.46 11 (MeOD); δ 8.99 (d, J =1.5 Hz, 1H), 8.50 (s, 1H), 8.36 (d, J = 9.9 Hz, 1H), mono-formate 8.20(dd, J = 2.3, 8.1 Hz, 1H), 7.54 (d, J = 8.3 Hz, 1H), 7.40-7.31 (m, 12H),7.02 (d, J = 8.1 Hz, 1H), 6.99-6.95 (m, 2H), 6.91-6.88 (m, 1H), 6.66 (d,J = 9.9 Hz, 1H), 5.39 (dd, J = 5.2, 7.7 Hz, 1H), 4.28 (s, 2H), 4.12-4.04(m, 4H), 3.88 (s, 2H), 3.59 (dd, J = 6.9, 6.9 Hz, 2H), 3.18-3.11 (m,4H), 2.53-2.43 (m, 2H), 2.14-2.05 (m, 2H), 1.83-1.76 (m, 1H), 1.71-1.64(m, 2H), 1.40-1.30 (m, 2H). 32D 2.53 11 (MeOD); δ 8.52 (s, 1H), 8.26 (d,J = 9.9 Hz, 1H), 7.46 (s, 1H), 7.42 (s, 2H), mono-formate 7.41-7.35 (m,7H), 7.35-7.30 (m, 3H), 7.24 (dd, J = 8.3, 8.3 Hz, 2H), 7.03-6.94 (m,3H), 6.90 (d, J = 8.6 Hz, 1H), 6.62 (d, J = 9.6 Hz, 1H), 5.33 (dd, J =6.6, 6.6 Hz, 1H), 4.21-4.14 (m, 4H), 4.11-4.03 (m, 4H), 3.80 (s, 2H),3.57 (dd, J = 6.8, 6.8 Hz, 2H), 3.14-3.04 (m, 4H), 2.37 (dd, J = 11.9,11.9 Hz, 2H), 2.12-2.06 (m, 2H), 1.77-1.70 (m, 1H), 1.68-1.60 (m, 2H),1.44 (t, J = 6.8 Hz, 3H), 1.37-1.27 (m, 2H). 32E 2.55 11 (MeOD); δ 8.39(s, 2H), 8.33 (d, J = 9.9 Hz, 1H), 7.85-7.81 (m, 2H), formate 7.69 (d, J= 8.1 Hz, 1H), 7.45 (s, 5H), 7.41-7.30 (m, 5H), 7.28-7.22 (m, 2H),7.03-6.95 (m, 3H), 6.90 (dd, J = 2.4, 8.5 Hz, 1H), 6.63 (d, J = 9.9 Hz,1H), 5.32 (dd, J = 4.3, 8.6 Hz, 1H), 4.16-4.10 (m, 6H), 4.05 (t, J = 6.1Hz, 2H), 3.57 (t, J = 6.9 Hz, 2H), 3.35 (br s, 2H), 3.10-3.00 (m, 2H),2.86-2.77 (m, 2H), 2.13-2.06 (m, 2H), 1.95-1.88 (m, 1H), 1.76 (d, J =13.4 Hz, 2H), 1.49-1.38 (m, 2H). 32F 2.51 11 (MeOD); δ 8.43 (s, 2H),8.31 (d, J = 9.6 Hz, 1H), 7.45 (s, 5H), 7.42-7.24 (m, formate 9H),7.05-6.96 (m, 3H), 6.92 (dd, J = 2.5, 8.3 Hz, 1H), 6.66 (d, J = 9.9 Hz,1H), 5.42-5.37 (m, 1H), 4.27 (s, 2H), 4.14-4.04 (m, 9H), 3.58 (dd, J =6.8, 6.8 Hz, 2H), 3.32-3.27 (m, 2H), 3.14 (d, J = 6.8 Hz, 2H), 2.83-2.73(m, 2H), 2.13-2.04 (m, 2H), 1.95-1.86 (m, 1H), 1.76 (d, J = 12.6 Hz,2H), 1.48-1.38 (m, 2H). 32G 2.55 11 (MeOD); δ 8.36 (s, 2H), 8.14 (d, J =9.9 Hz, 1H), 7.39 (s, 1H), 7.35-7.18 (m, formate 12H), 7.15-7.10 (m,2H), 6.92-6.83 (m, 3H), 6.78 (dd, J = 2.1, 8.0 Hz, 1H), 6.52 (d, J = 9.9Hz, 1H), 5.23 (dd, J = 4.5, 8.6 Hz, 1H), 4.71-4.64 (m, 1H), 4.12 (d, J =2.8 Hz, 2H), 4.00-3.91 (m, 4H), 3.82 (s, 2H), 3.45 (dd, J = 6.9, 6.9 Hz,2H), 3.09-3.02 (m, 4H), 2.43 (dd, J = 11.0, 12.0 Hz, 2H), 2.01-1.95 (m,2H), 1.74-1.67 (m, 1H), 1.58 (d, J = 13.1 Hz, 2H), 1.28-1.23 (m, 8H).32H 2.49 11 (MeOD); δ 8.46 (s, 2H), 8.32 (d, J = 9.9 Hz, 1H), 7.58 (d, J= 1.3 Hz, 1H), formate 7.46-7.23 (m, 14H), 7.04-6.96 (m, 3H), 6.92 (dd,J = 2.1, 8.0 Hz, 1H), 6.66 (d, J = 9.9 Hz, 1H), 5.34 (dd, J = 4.2, 9.0Hz, 1H), 4.14-4.04 (m, 8H), 3.56 (dd, J = 6.7, 6.7 Hz, 2H), 3.28-3.22(m, 2H), 3.06-3.01 (m, 2H), 2.75-2.65 (m, 2H), 2.09-2.05 (m, 2H),1.91-1.83 (m, 1H), 1.77-1.71 (m, 2H), 1.45-1.35 (m, 2H). 32I 2.48 11(MeOD) d 8.46 (s, 2H), 8.30 (d, J = 9.9 Hz, 1H), 7.43-7.31 (m, 12H),formate 7.28-7.23 (m, 2H), 7.04-6.96 (m, 3H), 6.91 (dd, J = 2.1, 8.0 Hz,1H), 6.65 (d, J = 9.9 Hz, 1H), 5.36 (t, J = 6.6 Hz, 1H), 4.17 (s, 2H),4.13-4.04 (m, 4H), 4.00 (s, 2H), 3.89 (s, 3H), 3.59 (dd, J = 6.7, 6.7Hz, 2H), 3.23 (d, J = 12.1 Hz, 2H), 3.10 (d, J = 6.1 Hz, 2H), 2.67-2.58(m, 2H), 2.10-2.05 (m, 2H), 1.90-1.82 (m, 1H), 1.72 (d, J = 12.6 Hz,2H), 1.43-1.32 (m, 2H). 32J 2.48 11 (MeOD); δ 8.50 (s, 2H), 8.30 (d, J =9.0 Hz, 1H), 7.45 (s, 1H), 7.41-7.32 (m, formate 12H), 7.09 (s, 1H),7.04-6.96 (m, 3H), 6.92 (dd, J = 2.0, 8.1 Hz, 1H), 6.66 (d, J = 9.9 Hz,1H), 5.34 (dd, J = 5.2, 8.0 Hz, 1H), 4.13-4.06 (m, 6H), 3.94 (s, 2H),3.87 (s, 3H), 3.57 (t, J = 6.8, 6.8 Hz, 2H), 3.22-3.09 (m, 2H),3.08-3.04 (m, 2H), 2.57 (dd, J = 11.7 Hz, 2H), 2.14-2.05 (m, 2H),1.88-1.80 (m, 1H), 1.68 (d, J = 12.1 Hz, 2H), 1.42-1.32 (m, 2H). 32K2.47 11 (MeOD); δ 8.66 (d, J = 1.5 Hz, 1H), 8.42 (s, 2H), 8.31 (d, J =9.9 Hz, 1H), formate 8.10 (d, J = 8.1 Hz, 1H), 8.02 (dd, J = 2.1, 8.0Hz, 1H), 7.44-7.37 (m, 6H), 7.37-7.22 (m, 6H), 7.10 (dd, J = 2.0, 2.0Hz, 1H), 7.02 (d, J = 8.3 Hz, 1H), 6.97-6.91 (m, 2H), 6.63 (d, J = 9.9Hz, 1H), 5.34 (dd, J = 4.5, 8.3 Hz, 1H), 4.18 (s, 2H), 4.13-4.05 (m,6H), 3.62 (t, J = 6.6, 6.6 Hz, 2H), 3.29-3.23 (m, 2H), 3.12-3.06 (m,2H), 2.69 (dd, J = 11.5, 11.5 Hz, 2H), 2.14-2.06 (m, 2H), 1.86-1.80 (m,1H), 1.72 (d, J = 13.6 Hz, 2H), 1.43-1.33 (m, 2H). 32L 2.49 11 (MeOD); δ8.50 (s, 1H), 8.34 (d, J = 9.9 Hz, 1H), 7.47-7.42 (m, 2H), mono-formate7.42-7.37 (m, 6H), 7.36-7.21 (m, 6H), 7.02-6.96 (m, 3H), 6.92-6.89 (m,1H), 6.64 (d, J = 9.9 Hz, 1H), 5.27 (dd, J = 4.0, 8.6 Hz, 1H), 4.13-4.01(m, 6H), 3.95 (s, 2H), 3.57 (t, J = 6.8 Hz, 2H), 3.22-3.15 (m, 2H),2.99-2.86 (m, 2H), 2.57 (dd, J = 10.0, 12.5 Hz, 2H), 2.12-2.05 (m, 2H),1.88-1.79 (m, 1H), 1.69 (d, J = 12.4 Hz, 2H), 1.42-1.32 (m, 2H). 32M2.53 11 (MeOD) d 8.48 (s, 1H), 8.33 (d, J = 9.9 Hz, 1H), 8.17 (d, J =1.3 Hz, 1H), mono-formate 8.04 (dd, J = 1.4, 8.0 Hz, 1H), 7.80 (d, J =8.1 Hz, 1H), 7.43-7.36 (m, 7H), 7.35-7.29 (m, 3H), 7.27-7.22 (m, 2H),7.02-6.96 (m, 3H), 6.91-6.88 (m, 1H), 6.63 (d, J = 9.9 Hz, 1H), 5.27(dd, J = 4.2, 8.5 Hz, 1H), 4.14-4.09 (m, 4H), 4.05 (t, J = 6.0 Hz, 2H),4.01 (s, 2H), 3.58 (t, J = 6.8 Hz, 2H), 3.24 (d, J = 12.1 Hz, 2H),3.01-2.89 (m, 2H), 2.68-2.60 (m, 2H), 2.13-2.05 (m, 2H), 1.90-1.82 (m,1H), 1.71 (d, J = 12.9 Hz, 2H), 1.44-1.34 (m, 2H). 33 7.28 7 (DMSO-d₆,90° C.); δ 8.23 (s, 2H), 8.19 (d, J = 10.1 Hz, 1H), 7.46 (d, J = 8.3 Hz,Formate 2H), 7.38-7.25 (m, 13H), 7.10 (d, J = 8.2 Hz, 1H), 6.98-6.91 (m,4H), 6.53 (d, J = 9.9 Hz, 1H), 5.19-5.43 (m, 1H), 5.09 (s, 2H),4.53-4.40 (m, 1H), 4.00 (d, J = 6.1 Hz, 2H), 3.62-3.50 (m, 1H), 3.40 (s,2H), 3.06-2.95 (m, 1H), 2.84 (d, J = 6.4 Hz, 2H), 2.76-2.63 (m, 4H),1.88-1.61 (m, 5H), 1.56-1.43 (m, 3H), 1.17-1.09 (m, 4H). 33A 2.52 1(DMSO-d₆); δ 8.35 (s, 2H), 8.26-824 (m, 1H), 7.51 (d, J = 8.1 Hz, 2H),Formate 7.18-7.26 (m, 15 H), 7.19-7.12 (m, 1H), 7.05-6.96 (m, 3H),6.61-6.59 (m, 1H), 5.31 (d, J = 6.6 Hz, 1H), 5.14 (s, 2H), 4.54-4.53 (m,1H), 4.05 (d, J = 6.3 Hz, 2H), 3.62-3.58 (m, 1H), 3.23 (s, 2H),3.04-2.78 (m, 8H), 1.93-1.84 (m, 2H), 1.81-1.76 (m, 1H), 1.59-1.52 (m,6H), 1.24-1.13 (m, 4H). 34 7.39 7 (DMSO-d₆, 90° C.); δ 8.63 (t, J = 7.2Hz, 1H), 8.22 (s, 2H), 8.17 (d, J = 9.9 Hz, Formate 1H), 7.80 (d, J =8.3 Hz, 2H), 7.34-7.20 (m, 11H), 7.18-7.14 (m, 1H), 7.10 (d, J = 8.3 Hz,1H), 6.95 (d, J = 8.2 Hz, 1H), 6.92-6.89 (m, 3H), 6.75 (d, J = 8.3 Hz,2H), 6.53 (d, J = 9.9 Hz, 1H), 5.15 (t, J = 6.3 Hz, 1H), 4.08-3.97 (m,4H), 3.64-3.58 (m, 2H), 3.00-2.90 (m, 2H), 2.86 (d, J = 6.5 Hz, 4H),2.71 (d, J = 11.4 Hz, 2H), 1.84-1.78 (m, 2H), 1.53-1.44 (m, 3H),1.16-1.06 (m, 2H). 35 2.50 11 (DMSO--d₆); δ 10.54-10.48 (m, 2H),9.57-9.47 (m, 1H), 8.64-8.64 (m, TFA 2H), 8.18 (d, J = 9.9 Hz, 1H),7.52-7.41 (m, 8H), 7.36-7.24 (m, 6H), 7.16 (d, J = 8.2 Hz, 1H),7.02-6.95 (m, 3H), 6.92 (d, J = 7.7 Hz, 1H), 6.73-6.63 (m, 1H), 6.59 (d,J = 9.9 Hz, 1H), 6.25-6.14 (m, 1H), 5.39-5.33 (m, 1H), 5.10 (s, 2H),4.54-4.42 (m, 1H), 4.26 (dt, J = 6.0, 18.4 Hz, 2H), 4.00 (d, J = 6.4 Hz,2H), 3.54-3.54 (m, 1H), 3.37-3.29 (m, 2H), 3.14-3.05 (m, 3H), 3.00-2.85(m, 4H), 2.10-2.04 (m, 1H), 1.90-1.79 (m, 2H), 1.77-1.64 (m, 3H),1.40-1.31 (m, 2H), 1.27-1.11 (m, 3H). 36 2.38 11 (DMSO-d₆, 100° C.); δ8.24 (d, J = 9.9 Hz, 1H), 7.53-7.49 (m, 5H), TFA 7.44-7.25 (m, 6H), 7.20(d, J = 8.3 Hz, 1H), 7.07-7.01 (m, 3H), 6.93-6.89 (m, 1H), 6.61 (d, J =9.9 Hz, 1H), 5.43 (dd, J = 4.7, 8.3 Hz, 1H), 4.75 (s, 2H), 4.28 (s, 2H),4.14-4.10 (m, 3H), 3.40-3.30 (m, 2H), 3.23-3.19 (m, 2H), 3.05-2.88 (m,6H), 2.14-2.05 (m, 1H), 2.00-1.76 (m, 6H), 1.59-1.47 (m, 2H), 1.33-1.18(m, 2H). 36A 2.53 11 (DMSO-d₆); δ 8.35 (s, 2H), 8.26 (d, J = 9.9 Hz,1H), 7.39-7.28 (m, 12H), Formate 7.18 (d, J = 8.3 Hz, 1H), 7.03 (d, J =8.1 Hz, 1H), 6.96 (d, J = 8.3 Hz, 1H), 6.93-6.87 (m, 2H), 6.60 (d, J =9.9 Hz, 1H), 5.31 (dd, J = 3.5, 8.8 Hz, 1H), 4.78 (d, J = 4.3 Hz, 2H),4.32 (d, J = 12.1 Hz, 1H), 4.05 (d, J = 6.3 Hz, 2H), 3.83 (d, J = 14.1Hz, 1H), 3.23 (s, 2H), 3.05-2.86 (m, 5H), 2.78 (d, J = 11.4 Hz, 2H),1.93-1.85 (m, 2H), 1.69 (d, J = 12.9 Hz, 2H), 1.58-1.48 (m, 7H),1.23-1.12 (m, 3H), 1.00-0.97 (m, 1H). 37 2.48 11 (MeOD); δ 8.37 (d, J =9.9 Hz, 1H), 7.83 (d, J = 8.3 Hz, 2H), 7.52-7.48 (m, TFA 6H), 7.44-7.23(m, 9H), 7.05 (d, J = 8.2 Hz, 1H), 6.99-6.94 (m, 2H), 6.91 (dd, J = 2.3,8.2 Hz, 1H), 6.70 (d, J = 9.9 Hz, 1H), 5.42 (dd, J = 5.5, 8.0 Hz, 1H),4.29 (dd, J = 6.6, 24.6 Hz, 2H), 4.12-4.00 (m, 4H), 3.56 (dd, J = 6.9,6.9 Hz, 2H), 3.50-3.35 (m, 4H), 3.31-3.28 (m, 2H), 3.20-3.10 (m, 2H),2.97 (dd, J = 10.7, 12.7 Hz, 2H), 2.11-2.04 (m, 2H), 1.94 (dd, J = 3.1,8.9 Hz, 1H), 1.83 (d, J = 14.6 Hz, 2H), 1.47-1.40 (m, 2H). 38 2.46 11(MeOD); δ 8.37 (d, J = 9.9 Hz, 1H), 7.83 (d, J = 8.3 Hz, 2H), 7.52-7.45(m, TFA 6H), 7.44-7.39 (m, 3H), 7.39-7.25 (m, 5H), 7.06-6.93 (m, 4H),6.70 (d, J = 9.8 Hz, 1H), 5.42 (dd, J = 5.6, 7.9 Hz, 1H), 4.26 (s, 2H),4.16-4.09 (m, 4H), 3.75 (dd, J = 5.7, 5.7 Hz, 2H), 3.50-3.35 (m, 5H),3.18-3.10 (m, 2H), 2.96 (dd, J = 12.5, 12.5 Hz, 2H), 2.00-1.78 (m, 4H),1.50-1.35 (m, 2H). 39 2.41 11 (MeOD); δ 8.28 (d, J = 9.9 Hz, 1H), 7.86(d, J = 8.2 Hz, 2H), 7.63 (d, J = 8.4 Hz, TFA 2H), 7.48 (s, 5H),7.39-7.26 (m, 10H), 7.03 (d, J = 8.3 Hz, 1H), 6.65 (dd, J = 1.7, 9.9 Hz,1H), 5.43 (dd, J = 5.8, 7.8 Hz, 1H), 4.39 (s, 2H), 4.28 (s, 2H), 4.08(d, J = 3.5 Hz, 2H), 3.62-3.55 (m, 2H), 3.49 (d, J = 11.8 Hz, 2H),3.27-3.23 (m, 2H), 3.01-2.89 (m, 4H), 1.95 (s, 1H), 1.82 (d, J = 14.1Hz, 2H), 1.49-1.38 (m, 1H). 40 2.47 11 (MeOD); δ 8.37 (d, J = 9.9 Hz,1H), 7.78 (d, J = 8.4 Hz, 2H), 7.48 (s, 5H), TFA 7.43-7.35 (m, 5H),7.35-7.25 (m, 7H), 7.05 (d, J = 8.2 Hz, 1H), 6.70 (d, J = 9.8 Hz, 1H),5.43 (dd, J = 6.7, 6.7 Hz, 1H), 4.27 (s, 2H), 4.10 (dd, J = 1.5, 6.3 Hz,2H), 3.60-3.53 (m, 2H), 3.49-3.43 (m, 2H), 3.41-3.35 (m, 2H), 3.21-3.10(m, 3H), 3.02-2.88 (m, 5H), 1.99-1.92 (m, 1H), 1.85-1.75 (m, 2H),1.50-1.37 (m, 2H). 41 2.47 11 (DMSO-d₆) δ 10.51 (s, 2H), 9.58 (s, 1H),9.19 (d, J = 27.2 Hz, 2H), 8.10 (d, TFA J = 9.9 Hz, 1H), 7.69 (d, J =7.3 Hz, 2H), 7.61 (d, J = 8.3 Hz, 2H), 7.48 (s, 5H), 7.32 (s, 6H),7.28-7.24 (m, 1H), 7.13 (d, J = 8.0 Hz, 1H), 7.01-6.96 (m, 1H),6.93-6.88 (m, 2H), 6.57 (d, J = 9.7 Hz, 1H), 6.19 (s, 1H), 5.36 (d, J =10.4 Hz, 1H), 4.41 (t, J = 8.6 Hz, 1H), 4.31-4.23 (m, 5H), 4.12 (d, J =7.2 Hz, 3H), 4.01 (d, J = 6.3 Hz, 2H), 3.89-3.85 (m, 1H), 3.05-3.02 (m,4H), 2.90-2.89 (m, 2H), 1.75 (d, J = 14.8 Hz, 3H), 1.37 (d, J = 13.3 Hz,2H), 1.29-1.21 (m, 2H). 42 2.46 11 (MeOD) δ 8.37 (d, J = 9.9 Hz, 1H),7.69-7.62 (m, 2H), 7.50 (dd, J = 4.0, 4.0 Hz, TFA 6H), 7.43 (dd, J =3.9, 8.2 Hz, 3H), 7.39-7.27 (m, 5H), 7.05 (d, J = 8.2 Hz, 1H), 7.03-6.91(m, 3H), 6.70 (d, J = 9.8 Hz, 1H), 5.45-5.40 (m, 1H), 4.53-4.48 (m, 1H),4.28 (s, 4H), 4.15-4.09 (m, 5H), 3.49-3.35 (m, 3H), 3.29 (d, J = 8.0 Hz,2H), 3.17-3.09 (m, 4H), 3.01-2.94 (m, 2H), 2.13-1.72 (m, 4H), 1.50-1.38(m, 2H). 42A 2.43 11 (MeOD); δ 8.53 (s, 1H), 8.20 (d, J = 9.9 Hz, 1H),7.52 (d, J = 1.9 Hz, 1H), mono-Formate 7.41-7.24 (m, 14H), 7.13 (dd, J =2.1, 2.1 Hz, 1H), 7.09 (d, J = 7.9 Hz, 1H), 7.04-7.01 (m, 2H), 6.63 (d,J = 9.9 Hz, 1H), 5.37 (dd, J = 6.5, 6.5 Hz, 1H), 4.68 (s, 2H), 4.23 (s,2H), 4.08 (d, J = 6.4 Hz, 2H), 3.89 (s, 3H), 3.77 (s, 2H), 3.14 (d, J =6.5 Hz, 2H), 3.05 (d, J = 11.8 Hz, 2H), 2.39-2.31 (m, 2H), 1.79-1.71 (m,1H), 1.61 (d, J = 12.7 Hz, 2H), 1.38-1.26 (m, 2H). 42B 2.49 11 (MeOD); δ8.55 (s, 1H), 8.27 (d, J = 9.9 Hz, 1H), 7.75 (d, J = 6.4 Hz, 1H),mono-Formate 7.39-7.29 (m, 11H), 7.23 (d, J = 8.7 Hz, 2H), 7.13-7.09 (m,2H), 7.05-7.00 (m, 2H), 6.63 (d, J = 9.8 Hz, 1H), 5.31 (dd, J = 5.6, 7.5Hz, 1H), 4.73 (s, 2H), 4.10-4.05 (m, 4H), 3.83 (s, 3H), 3.68 (s, 2H),3.07-2.96 (m, 4H), 2.24 (dd, J = 11.5, 11.5 Hz, 2H), 1.76-1.67 (m, 1H),1.58 (d, J = 12.0 Hz, 2H), 1.34-1.27 (m, 2H). 42C 2.57 11 (DMSO-d₆, 90°C.) d 8.69 (t, J = 5.9 Hz, 1H), 8.18 (d, J = 9.9 Hz, 1H), 7.88 (d, TFA J= 8.3 Hz, 2H), 7.46 (s, 5H), 7.38-7.24 (m, 12H), 7.16 (d, J = 8.3 Hz,1H), 7.02 (d, J = 8.2 Hz, 2H), 6.98-6.93 (m, 2H), 6.58 (d, J = 9.9 Hz,1H), 5.36 (dd, J = 4.4, 8.7 Hz, 1H), 5.03 (s, 2H), 4.51 (d, J = 6.0 Hz,2H), 4.19-4.15 (m, 2H), 4.08-4.03 (m, 2H), 3.35-3.29 (m, 4H), 3.24-3.18(m, 3H), 2.86-2.86 (m, 2H), 1.94-1.82 (m, 1H), 1.73-1.72 (m, 2H),1.42-1.42 (m, 2H). 42D 2.64 11 (DMSO-d₆) δ 10.53 (m, 2H), 9.45-9.40 (m,1H), 9.17 (m, 3H), 8.13 (d, TFA J = 9.9 Hz, 1H), 8.00 (d, J = 8.1 Hz,2H), 7.68 (d, J = 8.3 Hz, 2H), 7.52 (m, 5H), 7.42-7.35 (m, 10H), 7.17(d, J = 8.1 Hz, 1H), 7.04-6.93 (m, 4H), 6.67 (s, 1H), 6.63 (dd, J = 1.8,9.9 Hz, 1H), 6.23 (d, J = 1.0 Hz, 1H), 5.39 (d, J = 8.8 Hz, 1H), 5.06(s, 2H), 4.54 (d, J = 5.6 Hz, 2H), 4.38-4.25 (m, 4H), 4.08-4.01 (m, 2H),3.38 (m, 2H), 3.17-3.04 (m, 2H), 2.99-2.90 (m, 2H), 1.83-1.71 (m, 3H),1.44-1.35 (m, 2H). 42E 2.60 11 (MeOD); δ 8.38 (s, 2H), 8.19 (d, J = 9.9Hz, 1H), 7.81 (d, J = 7.9 Hz, 1H), formate 7.36-7.12 (m, 17H), 7.05 (d,J = 8.0 Hz, 1H), 6.93-6.83 (m, 4H), 6.54 (d, J = 9.8 Hz, 1H), 5.31-5.26(m, 1H), 4.94 (s, 2H), 4.51 (s, 2H), 4.12 (s, 2H), 3.97 (dd, J = 1.8,6.6 Hz, 2H), 3.91 (s, 2H), 3.88 (s, 3H), 3.14-3.02 (m, 4H), 2.54 (dd, J= 11.0, 11.0 Hz, 2H), 1.78-1.66 (m, 1H), 1.57 (d, J = 12.2 Hz, 2H),1.31-1.19 (m, 2H). 42F 2.59 11 (MeOD); δ 8.51 (s, 1H), 8.28 (d, J = 9.9Hz, 1H), 7.58 (s, 1H), 7.56-7.24 (m, mono-formate 16H), 7.05-6.92 (m,5H), 6.66 (d, J = 9.9 Hz, 1H), 5.45-5.37 (m, 1H), 5.05 (s, 2H), 4.61 (s,2H), 4.60 (s, 1H), 4.31 (s, 2H), 4.09 (dd, J = 1.3, 6.4 Hz, 2H), 3.98(s, 5H), 3.82 (s, 1H), 3.23-3.16 (m, 4H), 2.64-2.55 (m, 2H), 1.87-1.79(m, 1H), 1.67 (d, J = 12.9 Hz, 2H), 1.37 (q, J = 11.9 Hz, 2H).

Example 6. (S)-(1-Benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-((4-((3-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)propyl)carbamoyl)benzyl)oxy)phenyl)-2-phenylacetate(Compound 43)

Step 1; 4-(Chloromethyl)-N-(3,3-diethoxypropyl)benzamide

To a solution of 4-(chloromethyl)-benzoyl chloride (1.17 g, 6.21 mmol)in DCM (10 mL) was added a solution of 3,3-diethoxypropan-1-amine (0.914g, 6.21 mmol) and triethylamine (1.04 mL, 7.77 mmol) in DCM (10 mL). Thereaction mixture was stirred at room temperature for 3 hours. Thesolvent was evaporated under reduced pressure and the residue dissolvedin ethyl acetate. The organic phase was washed with 1M aqueous sodiumhydroxide, brine and dried over anhydrous magnesium sulfate and thefiltrate was evaporated under reduced pressure to afford the titlecompound (1.83 g, 99%).

¹H NMR (400 MHz, DMSO-d₆); δ 8.45 (dd, J=5.5, 5.5 Hz, 1H), 7.83 (d,J=8.4 Hz, 2H), 7.52 (d, J=8.3 Hz, 2H), 4.81 (s, 2H), 4.56 (dd, J=5.5,5.5 Hz, 1H), 3.59 (ddd, J=7.1, 9.5, 14.1 Hz, 2H), 3.45 (ddd, J=7.1, 9.5,14.1 Hz, 2H), 3.29 (dd, J=6.0, 7.4 Hz, 2H), 1.79 (dd, J=6.4, 13.6 Hz,2H), 1.12 (dd, J=7.0, 7.0 Hz, 6H).

Step 2; (2S)-(1-Benzylpiperidin-4-yl)methyl2-(3-((4-((3-ethoxy-3-propoxypropyl)carbamoyl)benzyl)oxy)phenyl)-2-hydroxy-2-phenylacetate

The title compound was prepared as described in Procedure 7 Step 4 with4-(chloromethyl)-N-(3,3-diethoxypropyl)benzamide replacing tert-butyl4-(bromomethyl)benzoate.

¹H NMR (400 MHz, DMSO-d₆); δ 8.43 (dd, J=5.5, 5.5 Hz, 1H), 7.83 (d,J=8.4 Hz, 2H), 7.47 (d, J=8.4 Hz, 2H), 7.26-7.20 (m, 11H), 6.97-6.90 (m,3H), 6.60 (s, 1H), 5.11 (s, 2H), 4.56 (dd, J=5.5, 5.5 Hz, 1H), 3.98 (d,J=6.3 Hz, 2H), 3.58 (ddd, J=7.1, 9.5, 14.1 Hz, 2H), 3.48-3.38 (m, 5H),2.73-2.67 (m, 2H), 1.85-1.76 (m, 3H), 1.52-1.44 (m, 3H), 1.12 (dd,J=7.0, 7.0 Hz, 6H).

Step 3; Compound (43)

The title compound (43) was prepared as described in Example 1 Step 9.

N Rt (min) Method NMR data (400 MHz) Salt (2 eq unless stated) 43 7.26 7(DMSO-d₆, 90° C.); δ 8.37 (dd, J = 5.6, 5.6 Hz, 1H), 8.18 (d, J = 9.9Hz, 1H), TFA 7.85 (d, J = 8.2 Hz, 2H), 7.51-7.44 (m, 8H), 7.38-7.24 (m,6H), 7.16 (d, J = 8.2 Hz, 1H), 7.04 (d, J = 2.0 Hz, 1H), 7.02-6.95 (m,3H), 6.56 (d, J = 9.9 Hz, 1H), 5.34 (dd, J = 4.5, 8.5 Hz, 1H), 5.12 (s,2H), 4.18 (s, 2H), 4.07 (s, 2H), 3.42-3.37 (m, 4H), 3.18-3.08 (m, 4H),2.88-2.88 (m, 2H), 2.01-1.93 (m, 2H), 1.87 (s, 1H), 1.74 (d, J = 13.2Hz, 2H), 1.42-1.42 (m, 2H).

Example 7. (R)-(1-Benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-((4-((3-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)propyl)carbamoyl)benzyl)oxy)phenyl)-2-phenylacetate(Compound 44)

Step 1; 4-(Chloromethyl)-N-(3,3-diethoxypropyl)benzamide

To a solution of 4-(chloromethyl)-benzoyl chloride (1.17 g, 6.21 mmol)in DCM (10 mL) was added a solution of 3,3-diethoxypropan-1-amine (0.914g, 6.21 mmol) and triethylamine (1.04 mL, 7.77 mmol) in DCM (10 mL). Thereaction mixture was stirred at room temperature for 3 hours. Thesolvent was evaporated under reduced pressure and the residue dissolvedin ethyl acetate. The organic phase was washed with 1M aqueous sodiumhydroxide, brine and dried over anhydrous magnesium sulfate and thefiltrate was evaporated under reduced pressure to afford the titlecompound (1.83 g, 99%).

¹H NMR (400 MHz, DMSO-d₆); δ 8.45 (dd, J=5.5, 5.5 Hz, 1H), 7.83 (d,J=8.4 Hz, 2H), 7.52 (d, J=8.3 Hz, 2H), 4.81 (s, 2H), 4.56 (dd, J=5.5,5.5 Hz, 1H), 3.59 (ddd, J=7.1, 9.5, 14.1 Hz, 2H), 3.45 (ddd, J=7.1, 9.5,14.1 Hz, 2H), 3.29 (dd, J=6.0, 7.4 Hz, 2H), 1.79 (dd, J=6.4, 13.6 Hz,2H), 1.12 (dd, J=7.0, 7.0 Hz, 6H).

Step 2; (2R)-(1-Benzylpiperidin-4-yl)methyl2-(3-((4-((3-ethoxy-3-propoxypropyl)carbamoyl)benzyl)oxy)phenyl)-2-hydroxy-2-phenylacetate

The title compound was prepared as described in Procedure 7 with(R)-2-hydroxy-2-(3-hydroxyphenyl)-2-phenylacetic acid replacing(S)-2-hydroxy-2-(3-hydroxyphenyl)-2-phenylacetic acid in Step 1 and4-(chloromethyl)-N-(3,3-diethoxypropyl)benzamide replacing tert-butyl4-(bromomethyl)benzoate in Step 4.

¹H NMR (400 MHz, DMSO-d₆); δ 8.43 (dd, J=5.5, 5.5 Hz, 1H), 7.83 (d,J=8.4 Hz, 2H), 7.47 (d, J=8.4 Hz, 2H), 7.26-7.20 (m, 11H), 6.97-6.90 (m,3H), 6.60 (s, 1H), 5.11 (s, 2H), 4.56 (dd, J=5.5, 5.5 Hz, 1H), 3.98 (d,J=6.3 Hz, 2H), 3.58 (ddd, J=7.1, 9.5, 14.1 Hz, 2H), 3.48-3.38 (m, 5H),2.73-2.67 (m, 2H), 1.85-1.76 (m, 3H), 1.52-1.44 (m, 3H), 1.12 (dd,J=7.0, 7.0 Hz, 6H).

Step 3; (Compound 44)

The title compound (44) was prepared as described in Example 1 Step 9.

N Rt (min) Method NMR data (400 MHz) Salt (2 eq unless stated) 44 7.25 6(DMSO-d6, 90° C.); δ 8.36 (dd, J = 5.5, 5.5 Hz, 1H), 8.18 (d, J = 9.9Hz, 1H), TFA 7.85 (d, J = 7.7 Hz, 2H), 7.48 (m, J = 5.5 Hz, 8H),7.38-7.24 (m, 6H), 7.16 (d, J = 8.2 Hz, 1H), 7.05 (s, 1H), 7.02-6.96 (m,3H), 6.57 (d, J = 9.8 Hz, 1H), 5.34 (dd, J = 4.5, 8.6 Hz, 1H), 5.12 (s,2H), 4.22 (s, 2H), 4.06 (s, 2H), 3.43-3.37 (m, 4H), 3.18-108 (m, 4H),2.87 (s, 2H), 2.05-1.94 (m, 2H), 1.88 (s, 1H), 1.77-1.74 (m, 2H),1.42-1.42 (m, 2H).

Example 8. (S)-(1-Benzylpiperidin-4-yl)methyl2-(3-((3-(benzyl(3-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)propyl)carbamoyl)benzyl)oxy)phenyl)-2-hydroxy-2-phenylacetate(Compound 45)

Step 1;N-(2-(1,3-Dioxolan-2-yl)ethyl)-N-benzyl-3-(chloromethyl)benzamide

The title compound was prepared as described in Example 5 Step 1 withN-benzyl-2-(1,3-dioxolan-2-yl)ethanamine replacing3,3-diethoxypropan-1-amine and 3-(chloromethyl)benzoyl chloridereplacing 4-(chloromethyl)benzoyl chloride.

Step 2; (S)-3-(2-(1,3-Dioxolan-2-yl)ethyl)(benzyl)carbamoyl)benzyl2-(3-((3-((2-(1,3-dioxolan-2-yl)ethyl)(benzyl)carbamoyl)benzyl)oxy)phenyl)-2-hydroxy-2-phenylacetate

The title compound was prepared as described in Example 4 Step 1 withN-(2-(1,3-dioxolan-2-yl)ethyl)-N-benzyl-3-(chloromethyl)benzamidereplacing 2-(4-chlorobutyl)-1,3-dioxolane.

Step 3; (Compound 45)

The title compound (45) was prepared as described in Example 4 Step 2through Step 4.

N Rt (min) Method NMR data (400 MHz) Salt (2 eq unless stated) 45 7.50 6(DMSO-d6, 90° C.); δ 8.15 (d, J = 9.4 Hz, 1H), 7.45 (d, J = 8.0 Hz, 8H),TFA 7.38-7.22 (m, 12H), 7.14 (d, J = 8.2 Hz, 1H), 7.04-6.92 (m, 4H),6.55 (d, J = 9.9 Hz, 1H), 5.30 (dd, J = 4.8, 7.8 Hz, 1H), 5.07 (s, 2H),4.57 (s, 2H), 4.07-4.07 (m, 2H), 3.43-3.40 (m, 2H), 3.16-108 (m, 7H),2.99 (s, 2H), 1.96 (dd, J = 7.5, 7.5 Hz, 3H), 1.73-1.69 (m, 2H),1.40-1.40 (m, 2H).

Example 9. (R)-quinuclidin-3-yl2-hydroxy-2-(3-(4-((5-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)pentyl)oxy)benzamido)phenyl)-2-phenylacetatediformate (Compound 46)

Step 1; Methyl 4-(4-(1,3-dioxolan-2-yl)butoxy)benzoate

To a solution of methyl 4-hydroxybenzoate (1 g, 6.57 mmol) in DMF (0.509ml) K₂CO₃ (1.045 g, 7.56 mmol) and 2-(4-bromobutyl)-1,3-dioxolane (1.649g, 7.89 mmol) were added. The mixture was stirred at RT overnight to getto completion. The mixture was poured onto saturated NaCl_(aq) (25 ml)and the aqueous phase was extracted with DCM (10 ml×3). The combinedorganic layers were dried over Na₂SO₄ and evaporated in vacuo to give acrude that was purified by flash chromatography (silica gel, eluents:100% n-Hex to 100% AcOEt) to afford methyl4-(4-(1,3-dioxolan-2-yl)butoxy)benzoate (1.6 g, 5.71 mmol, 87% yield).

UPLC-MS: 1.07 min, 249 [(M+H)−MeOH]+, method 2.

Step 2; 4-(4-(1,3-dioxolan-2-yl)butoxy)benzoic acid

To a solution of methyl 4-(4-(1,3-dioxolan-2-yl)butoxy)benzoate (1.13 g,4.03 mmol) in THF (24 ml, 293 mmol), LiOH 1M (1.209 ml, 1.209 mmol) wasadded and the mixture stirred at RT overnight. LiOH 1M (1.5 ml) wasadded and the mixture stirred at RT over the weekend to get tocompletion. NaHCO₃ was added till pH=6-7 and the aqueous phase extractedwith AcOEt (10 ml×3). The organic phase was dried over Na₂SO₄ andevaporated in vacuo to give a crude that was used without furtherpurifications for next steps.

UPLC-MS: 0.86 min, 267 [(M+H)]+, method 2.

Step 3; (R)-quinuclidin-3-yl 2-oxo-2-phenylacetate

To a solution of 2-oxo-2-phenylacetic acid (1 g, 6.66 mmol) in DCM (25ml, 389 mmol), oxalyl chloride (0.816 ml, 9.33 mmol) was added dropwiseat RT, and the mixture stirred for 20 min. Then (R)-quinuclidin-3-ol(0.847 g, 6.66 mmol) was added and the mixture stirred at RT for 2 hrs.DCM (50 ml) was added and the organic phase washed with NaHCO₃ saturatedsolution (30 ml×3). The organic layer was evaporated in vacuo to give(R)-quinuclidin-3-yl 2-oxo-2-phenylacetate (870 mg, 3.36 mmol, 50.4%yield) as an oily crude that was used without further purifications fornext steps.

UPLC-MS: 0.37 min, 260 [M+H]+, method 2.

Step 4; (R)-quinuclidin-3-yl2-(3-((tert-butoxycarbonyl)amino)phenyl)-2-hydroxy-2-phenylacetate

To a solution of (R)-quinuclidin-3-yl 2-oxo-2-phenylacetate (960 mg,3.70 mmol) in THF (20 ml, 244 mmol) at −15 deg,(3-(bis(trimethylsilyl)amino)phenyl)magnesium chloride 1M in THF (3.70ml, 3.70 mmol) was added dropwise and the mixture stirred for 15 min at0 deg, then allowed to warm to RT and stirred for 3 hrs at RT. Thereaction was quenched by addition of MeCN (2 ml) and partitioned betweenAcOEt (200 mL) and water (200 mL). Organic layer was washed twice withwater, once with sat NaCl, dried over Na₂SO₄ and dried under reducedpressure to give the desylilated compound. The crude was dissolved inDCM (20 ml) and di-tert-butyl dicarbonate (1.117 ml, 4.81 mmol), DMAP(90 mg, 0.740 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.838 ml,4.81 mmol) were added and the mixture stirred at RT overnight. DCM wasevaporated in vacuo to give a crude that was purified by flashchromatography (silica gel, eluents: DCM to 1/1 DCM/EtOH) to afford(R)-quinuclidin-3-yl2-(3-((tert-butoxycarbonyl)amino)phenyl)-2-hydroxy-2-phenylacetate (580mg, 1.282 mmol, 34.6% yield)

UPLC-MS: 0.64 min, 454 [M+H]+, method 2.

Step 5; (R)-quinuclidin-3-yl 2-(3-aminophenyl)-2-hydroxy-2-phenylacetatedihydrochloride

To a solution of (R)-quinuclidin-3-yl2-(3-((tert-butoxycarbonyl)amino)phenyl)-2-hydroxy-2-phenylacetate (500mg, 1.105 mmol) in acetonitrile (2 ml) HCl 4M in dioxane (1 ml, 32.9mmol) was added and the mixture stirred at RT for 2 hrs. The solvent wasevaporated in vacuo to give (R)-quinuclidin-3-yl2-(3-aminophenyl)-2-hydroxy-2-phenylacetate dihydrochloride (493 mg,1.160 mmol, 105% yield) that was used without further purifications fornext steps.

UPLC-MS: 0.50 min, 426 [M+H]+, method 1.

Step 6; (R)-quinuclidin-3-yl2-(3-(4-(4-(1,3-dioxolan-2-yl)butoxy)benzamido)phenyl)-2-hydroxy-2-phenylacetate

To a solution of 4-(4-(1,3-dioxolan-2-yl)butoxy)benzoic acid (324 mg,1.215 mmol)) in DMF (5 ml), HATU (504 mg, 1.326 mmol) and DIPEA (212 μl,1.215 mmol) were added. The mixture was stirred at RT for 30 min, then(R)-quinuclidin-3-yl 2-(3-aminophenyl)-2-hydroxy-2-phenylacetatedihydrochloride (470 mg, 1.105 mmol) in DMF (5 ml) and DIPEA (386 μl,2.210 mmol) were added to the mixture and stirred at RT on. The mixturewas purified by reverse phase chromatography (C-18 silica gel, eluents:100% H2O/Acetonitrile 95/5+HCOOH 0.1% to 100% H2O/ACN 5/95+HCOOH 0.1%)to afford (R)-quinuclidin-3-yl2-(3-(4-(4-(1,3-dioxolan-2-yl)butoxy)benzamido)phenyl)-2-hydroxy-2-phenylacetate(272 mg, 0.453 mmol, 41.0% yield).

UPLC-MS: 0.72 min, 601 [M+H]+, method 2.

Step 7; (R)-quinuclidin-3-yl2-hydroxy-2-(3-(4-((5-oxopentyl)oxy)benzamido)phenyl)-2-phenylacetate

To a solution of (R)-quinuclidin-3-yl2-(3-(4-(4-(1,3-dioxolan-2-yl)butoxy)benzamido)phenyl)-2-hydroxy-2-phenylacetate(272 mg, 0.453 mmol) in Acetonitrile (5.723 ml) HCl 2M (5.6 ml, 11.32mmol) was added and the mixture stirred at RT for 2 hrs. NaHCO₃saturated solution was added till pH=8 and the aqueous phase extractedwith AcOEt (50 ml×2). The organic phase was dried over Na₂SO₄ andevaporated in vacuo to give the title compound (195 mg, 0.350 mmol, 77%yield) that was used without further purifications for next steps.

UPLC-MS: 0.67 min, 557 [M+H]+, method 2.

Step 8; (R)-quinuclidin-3-yl2-(3-(4-((5-(((R)-2-(8-(benzyloxy)-2-oxo-1,2-dihydroquinolin-5-yl)-2-((tert-butyldimethylsilyl)oxy)ethyl)amino)pentyl)oxy)-benzamido)phenyl)-2-hydroxy-2-phenylacetate

To a solution of (R)-quinuclidin-3-yl2-hydroxy-2-(3-(4-((5-oxopentyl)oxy)benzamido)phenyl)-2-phenylacetate(195 mg, 0.350 mmol) in 1/1 solution DCM/EtOH (4 ml)(R)-5-(2-amino-1-((tert-butyldimethylsilyl)oxy)ethyl)-8-(benzyloxy)quinolin-2(1H)-one(223 mg, 0.525 mmol) and acetic acid (0.040 ml, 0.701 mmol) were added.Then a spatula of sodium sulfate was added and the mixture stirred at RTfor 15 min, sodium triacetoxyborohydride (371 mg, 1.752 mmol) was addedto the mixture and stirred at RT for 2 hrs, HCl 2M (2 ml) was added, themixture filtered and evaporated in vacuo to give a crude that waspurified by reverse phase chromatography (C-18 silica gel, eluents: 100%H2O/Acetonitrile 95/5+HCOOH 0.1% to 100% H2O/ACN 5/95+HCOOH 0.1%) toafford (R)-quinuclidin-3-yl2-(3-(4-((5-(((R)-2-(8-(benzyloxy)-2-oxo-1,2-dihydroquinolin-5-yl)-2-((tert-butyldimethylsilyl)oxy)ethyl)-amino)pentyl)oxy)benzamido)phenyl)-2-hydroxy-2-phenylacetate(150 mg, 0.155 mmol, 44.4% yield).

UPLC-MS: 1.43 min, 966 [M+H]+, method 2.

Step 9; (R)-quinuclidin-3-yl2-(3-(4-((5-(((R)-2-((tert-butyldimethylsilyl)oxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)pentyl)oxy)benzamido)phenyl)-2-hydroxy-2-phenylacetate

(R)-quinuclidin-3-yl2-(3-(4-((5-(((R)-2-(8-(benzyloxy)-2-oxo-1,2-dihydroquinolin-5-yl)-2-((tert-butyldimethylsilyl)oxy)ethyl)amino)pentyl)oxy)-benzamido)phenyl)-2-hydroxy-2-phenylacetate(150 mg, 0.155 mmol) and Pd—C 5% Enghelhart (50% water) (165 mg, 1.554μmol) were dissolved in MeOH (5 ml) and stirred at RT under H₂atmosphere for 2 hrs. The reaction was filtered over a small pad ofcelite and the filtrate dried under reduced pressure to give the titlecompound (70 mg, 0.080 mmol, 51.5% yield).

UPLC-MS: 1.17 min, 876 [M+H]+, method 4.

Step 10 (Compound 46)

To a solution of (R)-quinuclidin-3-yl2-(3-(4-((5-(((R)-2-((tert-butyldimethylsilyl)oxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)pentyl)oxy)benzamido)phenyl)-2-hydroxy-2-phenylacetate(70 mg, 0.080 mmol) in THF (2 ml) HCl 4M in dioxane (800 μl, 3.20 mmol)was added and the mixture stirred at RT for 6 hrs, then kept at −4 degovernight and then stirred again at RT for 6 hrs. Et20 (20 ml) was addedand removed under vacuum twice, then the residual solvent was evaporatedunder reduced pressure without warming to give a crude that was purifiedvia reverse phase preparative HPLC to afford the title compound (46) (12mg, 0.014 mmol, 17.59% yield).

N Rt (min) [M + H]+ Method NMR data (400 MHz) Salt (2 eq unless stated)46 3.99 761.0 5 (MeOH-d₄) δ 8.50 (br. s., 2 H), 8.36 (d, J = 9.87 Hz, 1H), 7.89 (dd, J = 8.88, Formate 7.23 Hz, 2 H), 7.64-7.16 (m, 9 H), 7.01(dd, J = 14.63, 8.39 Hz, 3 H), 6.68 (d, J = 9.87 Hz, 1 H), 5.46-5.34 (m,1 H), 5.16 (br. s., 1 H), 4.10 (t, J = 6.08 Hz, 2 H), 3.54-3.44 (m, 1H), 3.26-2.73 (m, 8 H), 2.34-2.12 (m, 1 H), 2.02-1.73 (m, 5 H),1.72-1.46 (m, 6 H)

Example 10. (1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-((4-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)butyl)carbamoyl)phenyl)-2-phenylacetatediformate (Compound 47)

Step 1; methyl 2-(3-formylphenyl)-2-hydroxy-2-phenylacetate

To a solution of methyl 2-oxo-2-phenylacetate (4.9 mL, 34.7 mmol) in 133mL of dry THF were added dropwise, at −20° C., 40 mL of 1M(3-(diethoxymethyl)phenyl)-magnesium bromide in THF (40.0 mmol) and themixture stirred overnight at RT. Reaction was quenched by the additionof saturated NH4Cl_(aq) and extracted with EtOAc. The organic layer waswashed with aqueous saturated NaCl_(aq) and evaporated under reducedpressure; the residue was dissolved in a mixture of 20 mL 2M HCl_(aq)and 20 mL of MeCN. The reaction was stirred for 2 h at RT, then dilutedwith AcOEt and 1M HCl_(aq), organic layer washed with saturatedNaCl_(aq) and dried over Na₂SO₄. After evaporation, the residue waspurified by flash chromatography (silica gel, eluents: hexane to 6/4AcOEt/hexane) to afford the title compound (6.8 g, 25.2 mmol, 75%yield).

UPLC-MS: 0.89 min, 253.1 [(M+H)—H₂O]+, method 1. a20140911_06

Step 2; 3-(1-hydroxy-2-methoxy-2-oxo-1-phenylethyl)benzoic acid

Methyl 2-(3-formylphenyl)-2-hydroxy-2-phenylacetate (3.8 g, 14.06 mmol),K₂H₂PO₄ (3.83 g, 28.1 mmol), 2-methyl-2-butene (14.89 ml, 141 mmol) andNaClO₂ (2.54 g, 28.1 mmol) were reacted in 36 mL of t-BuOH/water 1/1from 0° C. to RT for 4 h. Reaction was quenched by the addition of 1MHCl_(aq) until pH 6-7, diluted with water and extracted with AcOEt.Organic layer was dried over Na₂SO₄ and evaporated to dryness. The crudewas submitted to flash chromatography (silica gel, eluents: 100%DCM+0.2% AcOH to 80/20 DCM/EtOH +0.2% AcOH) to afford the title compound(4.1 g). The product obtained was used in the following steps withoutfurther purifications.

UPLC-MS: 0.79 min, 269.2 [(M+H)−H₂O]+, method 1.

Step 3; methyl2-hydroxy-2-(3-((4-oxobutyl)carbamoyl)phenyl)-2-phenylacetate

3-(1-hydroxy-2-methoxy-2-oxo-1-phenylethyl)benzoic acid 2 (2.6 g, 9.08mmol) and HATU (3.45 g, 9.08 mmol) were reacted for 30 min at 0° C.,then 4,4-diethoxybutan-1-amine (2.354 ml, 13.62 mmol) and DIEA (2.379ml, 13.62 mmol) were added and the mixture stirred at RT for 2 h.Reaction was quenched by the addition of 100 mL of 1M HCl_(aq) andstirred for 1 h RT, then extracted with AcOEt, organic layer dried overNa₂SO₄ and evaporated to dryness. The crude oil was purified by flashchromatography (silica gel, eluent: hexane to AcOEt) to give the titlecompound (2 g, 5.63 mmol, 62.0% yield). The product obtained was used inthe following steps without further purifications.

UPLC-MS: 0.73 min, 356.1 [M+H]+, method 1,

Step 4; methyl2-(3-((4-(((R)-2-(8-(benzyloxy)-2-oxo-1,2-dihydroquinolin-5-yl)-2-((tert-butyldimethylsilyl)oxy)ethyl)(tert-butoxycarbonyl)amino)butyl)carbamoyl)phenyl)-2-hydroxy-2-phenylacetate

1(R)-5-(2-amino-1-((tert-butyldimethylsilyl)oxy)ethyl)-8-(benzyloxy)quinolin-2(1H)-one(2.390 g, 5.63 mmol)) and methyl2-hydroxy-2-(3-((4-oxobutyl)carbamoyl)-phenyl)-2-phenylacetate (2 g,5.63 mmol) were reacted for 10 min at RT in 30 mL of DCM with a spatulatip of Na₂SO₄, then 0.3 mL of AcOH and NaB(OAc)₃H (2.39 g, 11.30 mm)were added and the mixture stirred at RT for 2 h. The reaction wasfiltered, dryed to half of the initial volume and diluted with 10 mL ofTHF and 10 mL of saturated NaHCO_(3 aq) and added with Boc₂O (2.46 g,11.30 mmol). The mixture was stirred vigorously for 0.5 h at RT, thendiluted with AcOEt and washed with saturated NaHCO_(3 aq), saturatedNaCl_(aq), dried over Na₂SO₄ and evaporated to dryness. The crude waspurified by flash chromatography (silica gel, DCM to AcOEt) to affordthe title compound (0.9 g, 1.042 mmol, 18.51% yield).

UPLC-MS: 1.56 min, 864.5 [M+H]+, method 1.

Step 5;2-(3-((4-(((R)-2-(8-(benzyloxy)-2-oxo-1,2-dihydroquinolin-5-yl)-2-((tert-butyldimethylsilyl)oxy)ethyl)(tert-butoxycarbonyl)amino)butyl)carbamoyl)phenyl)-2-hydroxy-2-phenylaceticacid

Methyl2-(3-((4-(((R)-2-(8-(benzyloxy)-2-oxo-1,2-dihydroquinolin-5-yl)-2-((tert-butyldimethylsilyl)oxy)ethyl)(tert-butoxycarbonyl)amino)butyl)carbamoyl)phenyl)-2-hydroxy-2-phenylacetate(0.9 g, 1.042 mmol) and LiOH (0.125 g, 5.21 mmol) were reacted in 7 mLof THF/water 1/1 for 1 h at RT. The reaction was quenched by theaddition of 0.1M HCl_(aq) and extracted with AcOEt, organic layer washedtwice with 0.1M HCl_(aq), once with saturated NaCl_(aq), dried overNa₂SO₄ and evaporated to dryness to give the title compound (869 mg,1.022 mmol, 98% yield).

UPLC-MS: 1.50 min, 850.3 [M+H]+, method 1.

Step 6; benzyl 4-(hydroxymethyl)piperidine-1-carboxylate

Piperidin-4-ylmethanol (5.2 g, 45.1 mmol) was dissolved in 60 mL of THFand 60 mL of saturated NaHCO₃ aq and then benzyl(2,5-dioxopyrrolidin-1-yl) carbonate (11.25 g, 45.1 mmol) addedportionwise. The mixture was stirred for 1 h at RT, partitioned betweenAcOEt and water, washed twice with 1M HCl_(aq) and saturated NaCl_(aq).Organic layer was dried over Na₂SO₄, evaporated under reduced pressureto afford the title compound (10.77 g, 43.2 mmol, 96% yield). Theproduct obtained was used in the following steps without furtherpurifications.

UPLC-MS; 0.80 min, 250.2 [M+H]+, method 1.

Step 7; benzyl4-((2-(3-((4-(((R)-2-(8-(benzyloxy)-2-oxo-1,2-dihydroquinolin-5-yl)-2-((tert-butyldimethylsilyl)oxy)ethyl)(tert-butoxycarbonyl)amino)butyl)carbamoyl)phenyl)-2-hydroxy-2-phenylacetoxy)methyl)piperidine-1-carboxylate

2-(3-((4-(((R)-2-(8-(benzyloxy)-2-oxo-1,2-dihydroquinolin-5-yl)-2-((tert-butyldimethylsilyl)oxy)ethyl)(tert-butoxycarbonyl)amino)butyl)carbamoyl)phenyl)-2-hydroxy-2-phenylaceticacid (400 mg, 0.471 mmol) and CDI (229 mg, 1,412 mmol) were reacted for30 min at RT, then benzyl 4-(hydroxymethyl)piperidine-1-carboxylate (469mg, 1.882 mmol) added and the reaction stirred for 2 h at 60° C., thenRT overnight. The crude was partitioned between saturated NaHCO_(3 aq)and AcOEt, organic layer dried over Na₂SO₄ and evaporated to dryness.The crude was purified by flash chromatography (silica gel, eluents: DCMto AcOEt) to afford the title compound (110 mg, 0.102 mmol, 21.62%yield).

UPLC-MS: 1.68 min, 1082.6 [M+H]+, method 1.

Step 8; piperidin-4-ylmethyl2-(3-((4-((tert-butoxycarbonyl)((R)-2-((tert-butyldimethylsilyl)oxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)butyl)carbamoyl)phenyl)-2-hydroxy-2-phenylacetateformate

Benzyl4-((2-(3-((4-(((R)-2-(8-(benzyloxy)-2-oxo-1,2-dihydroquinolin-5-yl)-2-((tert-butyldimethylsilyl)oxy)ethyl)(tert-butoxycarbonyl)amino)butyl)carbamoyl)phenyl)-2-hydroxy-2-phenylacetoxy)methyl)piperidine-1-carboxylate(110 mg, 0.102 mmol) was dissolved in 1 mL of MeOH, added of 7.80 μl ofHCOOH, Pd—C 10% wet (10.83 mg, 5.09 mol) and hydrogenated for 3 h at RTunder balloon pressure of hydrogen. Reaction mixture was filtered andreduced to dryness to give the title compound (120 mg). The productobtained was used in the following steps without further purifications.

UPLC-MS: 0.94 min, 857.6 [M+H]+, method 2.

Step 9; (1-benzylpiperidin-4-yl)methyl2-(3-((4-((tert-butoxycarbonyl)((R)-2-((tert-butyldimethylsilyl)oxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)butyl)carbamoyl)phenyl)-2-hydroxy-2-phenylacetate

Piperidin-4-ylmethyl2-(3-((4-((tert-butoxycarbonyl)((R)-2-((tert-butyldimethyl-silyl)oxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)butyl)carbamoyl)-phenyl)-2-hydroxy-2-phenylacetateformate (92 mg, 0.102 mmol) and benzaldehyde (13.45 μl, 0.132 mmol) weredissolved in 1 mL of DCM and stirred for 1 h at RT, then 7.58 μl of AcOHand Na(OAc)₃H (28.1 mg, 0.132 mmol) were and the mixture stirredovernight at RT. Further 1 eq. of aldehyde and Na(OAc)₃H were needed tobring reaction to completion. Reaction mixture was partitioned betweenAcOEt and saturated NaHCO_(3 aq), washed twice with saturatedNaHCO_(3 aq) and saturated NaCl_(aq), organic layer dried with Na₂SO₄and evaporated to dryness to give the title compound (100 mg). Theproduct obtained was used in the following steps without furtherpurifications.

UPLC-MS: 1.04 min, 946.6 [M+H]+, method 2.

Step 10; (Compound 47)

(1-Benzylpiperidin-4-yl)methyl2-(3-((4-((tert-butoxycarbonyl)((R)-2-((tert-butyldimethylsilyl)oxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)-butyl)carbamoyl)phenyl)-2-hydroxy-2-phenylacetate(100 mg, 0.106 mmol) was dissolved in 0.5 mL of MeCN and added with 2 mLof 5M HCl_(aq). The mixture was stirred for 1 h at RT and then submittedto reversed phase flash chromatography (C18 silica gel, eluents: from100% A to 100% B, A: water/MeCN 95/5+0.1% HCOOH, B: MeCN/water 95/5+0.1%HCOOH) to afford the title compound (47) (68 mg, 0.082 mmol, 78% yield).

Salt N Rt (min) [M + H]+ Method NMR data (400 MHz) (2 eq unless stated)47 3.83 733.1 5 (DMSO-d₆) δ 10.56-10.00 (bs, 1 H), 8.46 (s, 1 H), 8.13(m, 1 H), Formate 7.94-7.86 (m, 1 H), 7.74 (dt, J = 7.48, 1.36 Hz, 1 H),7.50-7.117 (m, 13 H), 7.09 (d, J = 7.89 Hz, 1 H), 6.94 (d, J = 7.89 Hz,1 H), 6.70 (br. s., 1 H), 6.52 (d, J = 9.87 Hz, 1 H), 5.15 (br. s., 1H), 4.45-4.19 (m, 1 H), 4.00 (m, 2 H), 3.23 (m, 7 H), 2.91-2.63 (m, 6H), 1.82 (t, J = 11.02 Hz, 2 H), 1.53 (d, J = 2.30 Hz, 5 H), 1.45 (d, J= 13.15 Hz, 2 H).

Example 11. (R)-quinuclidin-3-yl2-hydroxy-2-(3-((4-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)butyl)carbamoyl)phenyl)-2-phenylacetatediformate (compound 48)

Step 1; (R)-quinuclidin-3-yl2-(3-((4-(((R)-2-(8-(benzyloxy)-2-oxo-1,2-dihydroquinolin-5-yl)-2-((tert-butyldimethylsilyl)oxy)ethyl)(tert-butoxycarbonyl)amino)butyl)carbamoyl)phenyl)-2-hydroxy-2-phenylacetate

2-(3-((4-((R)-2-(8-(Benzyloxy)-2-oxo-1,2-dihydroquinolin-5-yl)-2-((tert-butyldimethylsilyl)oxy)ethyl)(tert-butoxycarbonyl)amino)butyl)carbamoyl)phenyl)-2-hydroxy-2-phenylaceticacid as described in Example 10, step 5 (150 mg, 0.176 mmol) and CDI(57.2 mg, 0.353 mmol) were reacted for 30 min at RT, then(R)-quinuclidin-3-ol (67.3 mg, 0.529 mmol) added and the reactionstirred overnight. The crude was partitioned between saturatedNaHCO_(3 aq) and AcOEt, organic layer was washed twice with water,saturated NaCl_(aq), dried over Na₂SO₄ and evaporated to dryness. Theresulting crude was submitted to flash chromatography (silica gel,eluents: from 100% AcOEt to 100% AcOEt/7N NH₃ in MeOH 9/1) to afford thetitle compound (93 mg, 0.097 mmol, 54.9% yield).

UPLC-MS: 1.13 min, 959.7 [M+H]+, method 2.

Step 2; (R)-quinuclidin-3-yl2-(3-((4-((tert-butoxycarbonyl)((R)-2-((tert-butyldimethylsilyl)oxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)butyl)carbamoyl)phenyl)-2-hydroxy-2-phenylacetateformate

(R)-quinuclidin-3-yl2-(3-((4-(((R)-2-(8-(benzyloxy)-2-oxo-1,2-dihydroquinolin-5-yl)-2-((tert-butyldimethylsilyl)oxy)ethyl)(tert-butoxycarbonyl)amino)butyl)carbamoyl)-phenyl)-2-hydroxy-2-phenylacetate(90 mg, 0.094 mmol), Pd/C (9.98 mg, 4.69 μmol) and HCOOH (7.20 μl, 0.188mmol) were dissolved in 0.94 mL of MeOH and hydrogenated under balloonpressure of H₂ for 2 h at RT until complete debenzylation. Reactionmixture was filtered on PTFE membrane and evaporated to dryness to givethe title compound (95 mg). The product obtained was used in thefollowing steps without further purifications.

UPLC-MS: 0.95 min, 869.6 [M+H]+, method 2.

Step 3; (compound 48)

The title example was made in a similar way as that of the compound ofexample 10, step 10 (86 mg, 0.094 mmol) to give the title compound (48)60 mg, 0.080 mmol, 85% yield).

UPLC-MS: 3.30 min (412%)-3.32 min (56.8%), 655.1 [M+H]+, Method 5

N Rt (min) [M + H]+ Method NMR data (400 MHz) Salt (2 eq unless stated)48 3.31 655.1 5 (DMSO-d6) δ ppm 10.44 (s, 2 H), 10.25 (br. s., 1 H),Formate 9.22-8.92 (m, 1 H), 8.75-8.48 (m, 2 H), 8.32-8.16 (m, 1 H), 7.95(dt, J = 5.59, 1.64 Hz, 1 H), 7.80 (t, J = 8.06 Hz, 1 H), 7.68-7.30 (m,7 H), 7.15 (d, J = 8.22 Hz, 1 H), 6.99 (d, J = 8.22 Hz, 1 H), 6.95-6.80(m, 1 H), 6.55 (d, J = 9.87 Hz, 1 H), 6.01-6.25 (m, 1 H), 5.41 (d, J =9.87 Hz, 1 H), 5.05-5.26 (m, 1 H), 3.59-3.79 (m, 2 H), 2.78-3.33 (m, 12H), 2.22 (br. s., 1 H), 1.32-2.00 (m, 8 H)

Example 12. (R)-1-methylpyrrolidin-3-yl2-hydroxy-2-(3-((4-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)butyl)carbamoyl)phenyl)-2-phenylacetatediformate (Compound 49)

Step 1; (R)-1-methylpyrrolidin-3-yl2-(3-((4-(((R)-2-(8-(benzyloxy)-2-oxo-1,2-dihydroquinolin-5-yl)-2-((tert-butyldimethylsilyl)oxy)ethyl)(tert-butoxycarbonyl)amino)butyl)carbamoyl)phenyl)-2-hydroxy-2-phenylacetate

The title compound was made in similar way as that of Example 11 Step 1from2-(3-((4-(((R)-2-(8-(benzyloxy)-2-oxo-1,2-dihydroquinolin-5-yl)-2-((tert-butyldimethylsilyl)oxy)ethyl)(tert-butoxycarbonyl)amino)butyl)carbamoyl)phenyl)-2-hydroxy-2-phenylaceticacid (150 mg, 0.176 mmol) to give the desired product (93 mg, 0.100mmol, 56.5% yield).

UPLC-MS: 1.12 min, 933.0 [M+H]+, method 2.

Step 2; (R)-1-methylpyrrolidin-3-yl2-(3-((4-((tert-butoxycarbonyl)((R)-2-((tert-butyldimethylsilyl)oxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)butyl)carbamoyl)phenyl)-2-hydroxy-2-phenylacetate

The title compound was made in similar way as that of Example 11, step 2from (R)-1-methylpyrrolidin-3-yl2-(3-((4-(((R)-2-(8-(benzyloxy)-2-oxo-1,2-dihydroquinolin-5-yl)-2-((tert-butyldimethylsilyl)oxy)ethyl)(tert-butoxycarbonyl)amino)butyl)carbamoyl)-phenyl)-2-hydroxy-2-phenylacetate(90 mg, 0.092 mmol), Pd—C 10% wet (9.78 mg, 4.60 μmol) and HCOOH (7.05μl, 0.184 mmol) to give the desired product (90 mg). The productobtained was used in the following steps without further purifications.

UPLC-MS: 0.93 min, 843.7 [M+H]+, method 2.

Step 3; (Compound 49)

The title example was made in a similar way as that of the compound ofexample 10, step 10 from (R)-1-methylpyrrolidin-3-yl2-(3-((4-((tert-butoxycarbonyl)((R)-2-((tert-butyldimethylsilyl)oxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)butyl)carbamoyl)phenyl)-2-hydroxy-2-phenylacetateformate (90 mg, 0.101 mmol) to give the desired compound (40 mg, 0.055mmol, 54.8% yield).

N Rt (min) [M + H]+ Method NMR data (400 MHz) Salt (2 eq unless stated)49 3.08 629.0 5 (DMSO-d₆) δ 10.10-10.50 (m, 1 H), 8.47 (s, 1 H), 8.21(s, 1 H), Formate 8.16 (d, J = 9.87 Hz, 1 H), 7.90 (q, J = 1.97 Hz, 1H), 7.75 (dd, J = 7.73, 1.48 Hz, 1 H), 7.24-7.50 (m, 7 H), 7.09 (d, J =8.22 Hz, 1 H), 6.94 (d, J = 7.89 Hz, 1 H), 6.68 (br. s., 1 H), 6.52 (d,J = 9.87 Hz, 1 H), 5.08-5.28 (m, 2 H), 2.88-2.80 (m, 2 H), 2.76 (d, J =6.58 Hz, 2 H), 2.65 (dd, J = 10.69, 6.08 Hz, 1 H), 2.54 (s, 1 H), 2.47(d, J = 10.85 Hz, 1 H), 2.25 (d, J = 7.23 Hz, 1 H), 2.18 (d, J = 3.29Hz, 4 H), 1.64 (td, J = 6.74, 2.63 Hz, 1 H), 1.54 (br. s., 4 H)

Example 13. (1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-((3-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzamido)propyl)-carbamoyl)phenyl)-2-phenylacetatediformate (Compound 50)

Step 1; Methyl2-(3-((3-((tert-butoxycarbonyl)amino)propyl)carbamoyl)phenyl)-2-hydroxy-2-phenylacetate

3-(1-Hydroxy-2-methoxy-2-oxo-1-phenylethyl)benzoic acid obtained as inExample 10, step 2 (500 mg, 1.747 mmol) and TBTU (561 mg, 1,747 mmol)were reacted for 5 min at RT in 5 mL DMF, then DIEA (0.305 ml, 1.747mmol) and tert-butyl (3-aminopropyl)carbamate (335 mg, 1.921 mmol) wereadded and the resulting mixture stirred at RT for 30 min. Reaction waspartitioned between 0.5M HCl_(aq) and AcOEt, organic phase washed threetimes with 0.5M HCl_(aq) and once with saturated NaHCO_(3 aq), once withsaturated NaCl_(aq) and dried over Na₂SO₄ to give the title compound(0.78 g, 1.763 mmol, quantitative yield). The product obtained was usedin the following steps without further purifications.

UPLC-MS: 0.99 min, 465 [M+Na]+, method 1.

Step 2;2-(3-((3-((tert-butoxycarbonyl)amino)propyl)carbamoyl)phenyl)-2-hydroxy-2-phenylaceticacid

Methyl2-(3-((3-((tert-butoxycarbonyl)amino)propyl)carbamoyl)phenyl)-2-hydroxy-2-phenylacetate(0.77 g, 1.740 mmol) and LiOH (0.208 g, 8.70 mmol) were reacted in 11 mLof THF/water 1/1 for 1 h at RT, then reaction quenched by the additionof 0.5M HCl_(aq) and extracted with AcOEt. Organic phase was washed withsaturated NaCl_(aq), dried over Na₂SO₄ and evaporated to dryness to givethe title compound (0.61 g, 1.424 mmol, 82% yield).

UPLC-MS: 0.86 min, 451.1 [M+Na]+, method 1.

Step 3; (1-benzylpiperidin-4-yl)methyl2-(3-((3-((tert-butoxycarbonyl)amino)propyl)-carbamoyl)phenyl)-2-hydroxy-2-phenylacetate

2-(3-((3-((tert-butoxycarbonyl)amino)propyl)carbamoyl)phenyl)-2-hydroxy-2-phenylaceticacid (300 mg, 0.700 mmol) and CDI (227 mg, 1.400 mmol) were reacted in4.7 mL of DMF at RT for 5 min, then (1-benzylpiperidin-4-yl)methanol(431 mg, 2,100 mmol) added and the mixture stirred at 45.0 overnight.Reaction was partitioned between saturated NaHCO₃ and AcOEt, and organicphase after evaporation was submitted to flash chromatography (silicagel, eluents: from 100% AcOEt to 80/20 AcOEt/NH3 7N in MeOH) to affordthe title compound (310 mg, 0.503 mmol, 71.9% yield). The productobtained was used in the following steps without further purifications.

UPLC-MS: 0.75 min, 616.2 [M+H]+, method 2.

Step 4; (1-benzylpiperidin-4-yl)methyl2-(3-((3-aminopropyl)carbamoyl)phenyl)-2-hydroxy-2-phenylacetate

(1-Benzylpiperidin-4-yl)methyl2-(3-((3-((tert-butoxylcarbonyl)amino)propyl)-carbamoyl)phenyl)-2-hydroxy-2-phenylacetate(310 mg, 0.503 mmol) was stirred for 1 h at RT in 4M HCl dioxane (8.00mmol) diluted with further 2.5 mL of dioxane, then dried under reducepressure and the residue triturated in Et₂O to give the title compound(0.22 g, 0.374 mmol, 74.2% yield) used in the next steps without furtherpurifications.

UPLC-MS: 0.38 min, 516.1 [M+H]+, method 2.

Step 5; (1-benzylpiperidin-4-yl)methyl2-(3-((3-(4-(((tert-butoxycarbonyl)((R)-2-((tert-butyldimethylsilyl)oxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzamido)propyl)-carbamoyl)phenyl)-2-hydroxy-2-phenylacetate

(R)-4-(((tert-butoxycarbonyl)(2-((tert-butyldimethylsilyl)oxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzoicacid, obtained as for

Procedure 4 Steps 1-5, (63 mg, 0.111 mmol) and TBTU (35.6 mg, 0.111mmol) was reacted for 5 min in 1.1 mL of DMF,(1-benzylpiperidin-4-yl)methyl2-(3-((3-aminopropyl)carbamoyl)phenyl)-2-hydroxy-2-phenylacetatediformate (85 mg, 0.144 mmol) and DIEA (58.0 μl, 0.332 mmol) were addedand the mixture stirred for 1 h at 60° C. Reaction was partitionedbetween AcOEt and saturated NaHCO₃, washed twice with water, saturatedNaCl_(aq), organic layer dried over Na₂SO₄ and evaporated to dryness.The resulting crude (110 mg, 0.103 mmol, 93% yield) was used in the nextstep without further purifications.

UPLC-MS: 1.06 min, 1066.2 [M+H]+, method 2.

Step 6; (Compound 50)

The title example was made in a similar way as that of the compound ofexample 10, step 10, from (1-benzylpiperidin-4-yl)methyl2-(3-((3-(4-(((tert-butoxycarbonyl)((R)-2-((tert-butyldimethylsilyl)oxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)-amino)methyl)benzamido)propyl)carbamoyl)phenyl)-2-hydroxy-2-phenylacetate(108 mg, 0.101 mmol) to give the title compound (50) (22 mg, 0.023 mmol,23.01% yield).

Salt N Rt (min) [M + H]+ Method NMR data (400 MHz) (2 eq unless stated)50 3.91 852.1 5 (DMSO-d6) δ ppm 10.54-9.76 (bs, 2 H), 8.66-8.38 (m, 2H), Formate 8.23-8.05 (m, 2 H), 7.90 (s, 1 H), 7.80 (d, J = 7.94 Hz, 3H), 7.52-7.14 (m, 15 H), 7.07 (d, J = 8.38 Hz, 1 H), 6.91 (d, J = 8.38Hz, 1 H), 6.73 (s, 1 H), 6.48 (d, J = 9.70 Hz, 1 H), 5.70-5.35 (m, 1 H),5.53-4.94 (m, 1 H), 4.23-4.45 (m, 1 H), 4.00 (d, J = 6.62 Hz, 2 H), 3.88(br. s., 2 H), 3.38 (m, 8 H), 2.72 (br. s., 4 H), 1.75 (s, 4 H),164-1.43 (m, 3 H)

Example 14. (1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(4-((5-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)pentyl)oxy)phenyl)-2-phenylacetatediformate (Compound 51)

Step 1; methyl 2-(4-(benzyloxy)phenyl)-2-hydroxy-2-phenylacetate

To a solution of methyl 2-oxo-2-phenylacetate (12.83 ml, 91 mmol) in 350mL of THF, 100 mL of a solution 1M (4-(benzyloxy)phenyl)magnesiumbromide (100 mmol) in THF was added dropwise at 0° C. over 30 min andstirred overnight at RT. Reaction was partitioned between AcOEt andsaturated NaCl_(aq), organic layer dried over Na₂SO₄ and evaporated todryness. The residue was crystallised in Et₂O to afford the titlecompound (15 g, 43.1 mmol, 47.4% yield).

UPLC-MS: 1.24 min, 331.2 [(M+H)−H2O]+, method 1.

Step 2; methyl 2-hydroxy-2-(4-hydroxyphenyl)-2-phenylacetate

Methyl 2-(4-(benzyloxy)phenyl)-2-hydroxy-2-phenylacetate (5 g, 14.35mmol) was dissolved in 100 mL of a mixture ethanol/AcOEt 6/4, added withPd—C 5% wet (3.05 g, 0.718 mmol) and stirred under 25 psi of hydrogenfor 2 h at RT. Reaction mixture was filtered on PTFE membrane andevaporated to dryness to give the crude, that was recrystallized iniPr₂O to afford the title compound (2.95 g, 11.43 mmol, 79.6% yield).

UPLC-MS: 0.76 min, 241.1 [(M+H)−H2O]+, method 1,

Step 3; methyl2-(4-(4-(1,3-dioxolan-2-yl)butoxy)phenyl)-2-hydroxy-2-phenylacetate(343-28-1)

Methyl 2-hydroxy-2-(4-hydroxyphenyl)-2-phenylacetate (1 g, 3.87 mmol)and 2-(4-bromobutyl)-1,3-dioxolane (0.616 ml, 4.07 mmol) were reacted in15.5 mL of at 80° C. for 8 h and RT overnight. Reaction mixture waspartitioned between water and AcOEt, washed twice with water and oncewith saturated NaCl_(aq). Organic layer was dried over Na₂SO₄ andevaporate to dryness to give the title compound (1.54 g, 3.99 mmol, 103%yield). The product obtained was used in the following steps withoutfurther purifications.

UPLC-MS: 1.12 min, 369.3 [(M+H)−H2O]+, method 1.

Step 4; methyl 2-hydroxy-2-(4-((5-oxopentyl)oxy)phenyl)-2-phenylacetate

Methyl2-(4-(4-(1,3-dioxolan-2-yl)butoxy)phenyl)-2-hydroxy-2-phenylacetate(1.50 g, 3.88 mmol) was dissolved in 19.4 mL of a mixture ACN/1MHCl_(aq) and stirred for 6 h at RT. Reaction was partitioned in AcOEtand washed three times with water and once with saturated NaCl_(aq).Organic layer was dried over Na₂SO₄ and evaporated to dryness to givethe title compound (1.12 g, 3.27 mmol, 84% yield). The product obtainedwas used in the following steps without further purifications.

UPLC-MS: 1.04 min, 325.2 [(M+H)−H2O]+, method 1.

Step 5; methyl2-(4-((5-(((R)-2-(8-(benzyloxy)-2-oxo-1,2-dihydroquinolin-5-yl)-2-((tert-butyldimethylsilyl)oxy)ethyl)(tert-butoxycarbonyl)amino)pentyl)oxy)phenyl)-2-hydroxy-2-phenylacetate

(R)-5-(2-amino-1-((tert-butyldimethylsilyl)oxy)ethyl)-8-(benzyloxy)quinolin-2(1H)-one(1.637 g, 3.86 mmol) and methyl2-hydroxy-2-(4-((5-oxopentyl)oxy)phenyl)-2-phenylacetate (1.10 g, 3.21mmol) were reacted for 1 h at RT in 16 mL of DCM with a spatula tip ofNa₂SO₄, then AcOH (0.184 ml, 3.21 mmol) and Na(OAc)₃H (1.362 g, 6.43mmol) were added in sequence and the mixture stirred for 3 h at RT. Thereaction was cooled to 0° C. before addition of TEA (0.448 ml, 3.21mmol) and di-tert-butyl dicarbonate (0.746 ml, 3.21 mmol), then thereaction was stirred for further 2 h at RT. The mixture was partitionedbetween AcOEt and washed three times with 0.2M HCl_(aq), twice withwater and once with saturated NaCl_(aq). Organic layer was dried overNa₂SO₄ and evaporated to dryness to give a crude that after purificationby flash chromatography (silica gel—eluents: hexane to hexane/THF)afforded the title compound (1.33 g, 1.563 mmol, 48.6% yield).

UPLC-MS: 1.78 min, 873.7 [M+Na]+, method 2.

Step 6;2-(4-((5-(((R)-2-(8-(benzyloxy)-2-oxo-1,2-dihydroquinolin-5-yl)-2-((tert-butyldimethylsilyl)oxy)ethyl)(tert-butoxycarbonyl)amino)pentyl)oxy)phenyl)-2-hydroxy-2-phenylaceticacid

The title compound was made in a similar way as that of the Example 10,step 5 from methyl2-(4-((5-(((R)-2-(8-(benzyloxy)-2-oxo-1,2-dihydroquinolin-5-yl)-2-((tert-butyldimethylsilyl)oxy)ethyl)(tert-butoxycarbonyl)amino)pentyl)oxy)phenyl)-2-hydroxy-2-phenylacetate(1.33 g, 1.563 mmol) and LiOH (0.187 g, 7.81 mmol) to give the desiredproduct (1.1 g, 1.314 mmol, 84% yield).

UPLC-MS: 1.68 min, 838.2 [M+H]+, method 1.20141106_16

Step 7; benzyl4-((2-(4-((5-(((R)-2-(8-(benzyloxy)-2-oxo-1,2-dihydroquinolin-5-yl)-2-((tert-butyldimethylsilyl)oxy)ethyl)(tert-butoxycarbonyl)amino)pentyl)oxy)phenyl)-2-hydroxy-2-phenylacetoxy)methyl)piperidine-1-carboxylate

The title compound was made in a similar way as that of the compound ofExample 10, step 7 from2-(4-((5-(((R)-2-(8-(benzyloxy)-2-oxo-1,2-dihydroquinolin-5-yl)-2-((tert-butyldimethylsilyl)oxy)ethyl)(tert-butoxycarbonyl)amino)pentyl)oxy)phenyl)-2-hydroxy-2-phenylaceticacid (200 mg, 0.239 mmol) to give the desired product (98 mg, 0.092mmol, 38.4% yield).

UPLC-MS: 3.25 min, 1068.5 [M+H]+, method 3.

Step 8; piperidin-4-ylmethyl2-(4-((5-((tert-butoxycarbonyl)((R)-2-((tert-butyldimethylsilyl)oxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)pentyl)oxy)phenyl)-2-hydroxy-2-phenylacetate

The title compound was made in a similar way as that of the Example 10,step 8 from benzyl4-((2-(4-((5-(((R)-2-(8-(benzyloxy)-2-oxo-1,2-dihydroquinolin-5-yl)-2-((tert-butyldimethylsilyl)oxy)ethyl)(tert-butoxycarbonyl)amino)pentyl)oxy)phenyl)-2-hydroxy-2-phenylacetoxy)methyl)piperidine-1-carboxylate(98 mg, 0.092 mmol), Pd—C 10% wet (9.76 mg, 4.59 μmol), and HCOOH (7.04μl, 0.183 mmol) to give the desired product (73 mg, 0.082 mmol, 89%yield). The product obtained was used in the following steps withoutfurther purifications.

UPLC-MS; 1.08 min, 844.7 [M+H]+, method 2.

Step 9; (1-benzylpiperidin-4-yl)methyl2-(4-((5-((tert-butoxycarbonyl)((R)-2-((tert-butyldimethylsilyl)oxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)pentyl)oxy)phenyl)-2-hydroxy-2-phenylacetate

The title compound was made in a similar way as that of the Example 10,step 9 from (1-benzylpiperidin-4-yl)methyl2-(4-((5-((tert-butoxycarbonyl)((R)-2-((tert-butyldimethylsilyl)oxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)-pentyl)oxy)phenyl)-2-hydroxy-2-phenylacetate(73 mg, 0.082 mmol), benzaldehyde (26.1 mg, 0.246 mmol), AcOH (9.39 μl,0.164 mmol) and NaB(OAc)₃H (52.1 mg, 0.246 mmol) to give the desiredproduct (77 mg). The product obtained was used in the following stepswithout further purifications.

UPLC-MS: 1.17 min, 934.7 [M+H]+, method 2.

Step 10; (Compound 51)

The title example was made in a similar way as that of the example 10,step 10 from (1-benzylpiperidin-4-yl)methyl2-(4-((5-((tert-butoxycarbonyl)((R)-2-((tert-butyldimethylsilyl)oxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)-pentyl)oxy)phenyl)-2-hydroxy-2-phenylacetate(77 mg, 0.082 mmol) to give the title product (51) (28 mg, 0.037 mmol,44.4% yield).

N Rt (min) [M + H]+ Method NMR data (400 MHz) Salt (2 eq unless stated)51 4.15 720 5 (DMSO-d6) δ ppm 10.51-10.21 (bs, 1 H), 8.27-8.10 (m, 2 H),Formate 7.40-7.18 (m, 12 H), 7.11 (d, J = 8.22 Hz, 1 H), 6.95 (d, J =8.22 Hz, 1 H), 6.90-6.82 (m, 2 H), 6.54 (d, J = 9.87 Hz, 1 H), 6.42 (br.s., 1 H), 5.19 (br. s., 1 H), 4.02-3.90 (m, 4 H), 3.41-3.35 (m, 2 H),2.68-2.96 (m, 6 H), 1.91-1.39 (m, 10 H), 1.15-1.07 (m, 2 H)

Example 15. (R)-quinuclidin-3-yl2-hydroxy-2-(4-((5-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)pentyl)oxy)phenyl)-2-phenylacetatediformate (Compound 52)

Step 1; (R)-quinuclidin-3-yl2-(4-((5-(((R)-2-(8-(benzyloxy)-2-oxo-1,2-dihydroquinolin-5-yl)-2-((tert-butyldimethylsilyl)oxy)ethyl)(tert-butoxycarbonyl)amino)-pentyl)oxy)phenyl)-2-hydroxy-2-phenylacetate

The title compound was made in a similar way as that of the Example 14,step 7 to give the desired product (138 mg, 0.146 mmol, 81% yield).

UPLC-MS: 1.27 min, 946.7 [M+H]+, method 2.

Step 2; (R)-quinuclidin-3-yl2-(4-((5-((tert-butoxycarbonyl)((R)-2-((tert-butyldimethyl-silyl)oxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)pentyl)oxy)phenyl)-2-hydroxy-2-phenylacetate

The title compound was made in a similar way as that of the Example 14,step 8 from (R)-quinuclidin-3-yl2-(4-((5-(((R)-2-(8-(benzyloxy)-2-oxo-1,2-dihydroquinolin-5-yl)-2-((tert-butyldimethylsilyl)oxy)ethyl)(tert-butoxycarbonyl)amino)pentyl)oxy)phenyl)-2-hydroxy-2-phenylacetate(138 mg, 0.146 mmol), Pd—C 10% wet (15.52 mg, 7.29 μmol) and HCOOH(11.19 μl, 0.292 mmol) to give the desired product (150 mg). The productobtained was used in the following step without further purifications.

UPLC-MS: 1.09 min, 856.7 [M+H]+, method 2.

Step 3; (compound 52)

The title example was made in a similar way as that of the compound ofexample 10, step 10, from (R)-quinuclidin-3-yl2-(4-((5-((tert-butoxycarbonyl)((R)-2-((tert-butyldimethylsilyl)oxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)pentyl)oxy)phenyl)-2-hydroxy-2-phenylacetateformate (132 mg, 0.146 mmol) to give the title product (52) (68 mg,0.099 mmol, 67.6% yield).

N Rt (min) [M + H]+ Method NMR data (400 MHz) Salt (2 eq unless stated)52 3.64 642.0 5 (DMSO-d6) δ ppm 10.59-10.24 (bs, 1 H), 8.19 (d, J =10.19 Hz, Formate 1 H), 8.15 (s, 1 H), 7.38-7.27 (m, 5 H), 7.25 (d, J =8.88 Hz, 2 H), 7.14 (d, J = 8.22 Hz, 1 H), 6.98 (d, J = 8.22 Hz, 1 H),6.92-6.83 (m, 2 H), 6.56 (d, J = 9.87 Hz, 1 H), 6.45 (br. s., 1 H), 5.32(dd, J = 9.87, 2.63 Hz, 1 H), 4.92-4.71 (m, 1 H), 4.44-4.21 (m, 1 H),4.05-3.89 (m, 2 H), 3.18 (dd, J = 13.98, 8.39 Hz, 2 H), 3.10-2.88 (m, 5H), 2.77-2.58 (m, 3 H), 1.92 (br. s., 1 H), 1.76-1.34 (m, 8 H)

Example 16. (1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(4-((4-((4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzamido)methyl)-benzyl)oxy)phenyl)-2-phenylacetatediformate (Compound 53)

Step 1; methyl2-(4-((4-(((tert-butoxycarbonyl)amino)methyl)benzyl)oxy)phenyl)-2-hydroxy-2-phenylacetate

Methyl 2-hydroxy-2-(4-hydroxyphenyl)-2-phenylacetate obtained as inExample 14, step 2 (0.5 g, 1.936 mmol), tert-butyl4-(bromomethyl)benzylcarbamate (0.581 g, 1.936 mmol) and K₂CO₃ (0.268 g,1.936 mmol) were reacted in 9.7 mL DMF at 80° C. for 3 h. Reaction waspartitioned between water and AcOEt, washed three times with water andsaturated NaCl_(aq), dried over Na₂SO₄ and evaporated to dryness. Theresidue was purified by flash column chromatography (silica gel;eluents: hexane to 50/50 hexane/AcOEt) to afford the title compound(1.42 g, 93%).

UPLC-MS: 1.30 min, 460.0 [(M+H)−H2O]+, method 2.

Step 2;2-(4-((4-(((tert-butoxycarbonyl)amino)methyl)benzyl)oxy)phenyl)-2-hydroxy-2-phenylaceticacid

The title compound was made in a similar way as that of the example 10,step 5 from methyl2-(4-((4-(((tert-butoxycarbonyl)amino)methyl)benzyl)oxy)phenyl)-2-hydroxy-2-phenylacetate(0.65 g, 1.361 mmol) and LiOH (0.163 g, 6.81 mmol) to give the desiredproduct (673 mg, 1.452 mmol, 107% yield).

UPLC-MS: 2.28 min, 446.0 [(M+H)−H2O]+, method 4.

Step 3; 2 (1-benzylpiperidin-4-yl)methyl2-(4-((4-(((tert-butoxycarbonyl)amino)methyl)-benzyl)oxy)phenyl)-2-hydroxy-2-phenylacetate

The title intermediate was made in a similar way as that of the compoundof Example 10, step 7 from2-(4-((4-(((tert-butoxycarbonyl)amino)methyl)benzyl)oxy)-phenyl)-2-hydroxy-2-phenylaceticacid (630 mg, 1.359 mmol), CDI (661 mg, 4.08 mmol) and(1-benzylpiperidin-4-yl)methanol (1116 mg, 5.44 mmol) to give thedesired product (520 mg, 0.799 mmol, 58.8% yield).

UPLC-MS: 0.92 min, 651.1 [M+H]+, method 2.

Step 4; (1-benzylpiperidin-4-yl)methyl2-(4-((4-(aminomethyl)benzyl)oxy)phenyl)-2-hydroxy-2-phenylacetate bishydrochloride

The title compound was made in a similar way as that of the Example 10,step 10 from 2 (1-benzylpiperidin-4-yl)methyl2-(4-((4-(((tert-butoxycarbonyl)amino)methyl)-benzyl)oxy)phenyl)-2-hydroxy-2-phenylacetate(520 mg, 0.799 mmol) to give the title compound (357 mg, 0.572 mmol,71.6% yield).

UPLC-MS: 0.49 min, 551.1 [M+H]+, method 2.

Step 5; (1-benzylpiperidin-4-yl)methyl2-(4-((4-((4-(((tert-butoxycarbonyl)((R)-2-((tert-butyldimethylsilyl)oxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)-methyl)benzamido)methyl)benzyl)oxy)phenyl)-2-hydroxy-2-phenylacetate

(R)-4-(((tert-butoxycarbonyl)(2-((tert-butyldimethylsilyl)oxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzoicacid, obtained as described in Procedure 4, steps 1-5, (50 mg, 0.264mmol), (1-benzylpiperidin-4-yl)methyl2-(4-((4-(aminomethyl)benzyl)oxy)phenyl)-2-hydroxy-2-phenylacetate bishydrochloride (164 mg, 0.264 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (46.3mg, 0.343 mmol), DMAP (4 mg, 0.033 mmol) and DIEA (0.138 ml, 0.791 mmol)were stirred for 5 min in 3 mL of DMF, then EDC (65.7 mg, 0.343 mmol)added and the mixture stirred overnight at RT. Reaction mixture waspartitioned between saturated NaHCO_(3 aq) and AcOEt, organic layerwashed three times with water and saturated NaCl_(aq), dried over Na₂SO₄and evaporated to dryness to give the crude (292 mg). The crude obtainedwas used in the following step without further purifications.

UPLC-MS: 1.14 min, 1102.1 [M+H]+, method 2.

Step 6; (Compound 53)

The title example was made in a similar way as that of the example 10,step 10 from 1-benzylpiperidin-4-yl)methyl2-(4-((4-((4-(((tert-butoxycarbonyl)((R)-2-((tert-butyldimethylsilyl)oxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)-methyl)benzamido)methyl)benzyl)oxy)phenyl)-2-hydroxy-2-phenylacetate(290 mg, 0.263 mmol) to give the title product (53) (62 mg, 0.063 mmol,24.05% yield).

N R_(t) (min) [M + H]+ Method NMR data (400 MHz) Salt 2 eq unless stated53 4.72 887.0 5 (DMSO-d6) d ppm 10.33 (br. s., 1 H), 9.00 (t, J = 5.95Hz, 1 Formate H), 8.22-8.01 (m, 2 H), 7.85 (d, J = 7.94 Hz, 2 H),7.49-6.83 (m, 22 H), 6.60-6.34 (m, 2 H), 5.20-4.97 (m, 3 H), 4.47 (d, J= 5.73 Hz, 2 H), 4.34 (br. s., 1 H), 3.97 (d, J = 6.17 Hz, 2 H), 3.89(s, 2 H), 3.59-3.37 (m, 5 H), 2.84-2.59 (m, 4 H), 1.84 (t, J = 11.03 Hz,2 H), 1.58-1.35 (m, 3 H), 1.19-0.97 (m, 4 H)

Example 17. (1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-((((5-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)pentyl)oxy)carbonyl)amino)-phenyl)-2-phenylacetatebis hydrochloride (Compound 54)

Step 1; Methyl 2-(3-aminophenyl)-2-hydroxy-2-phenylacetate

Methyl 2-oxo-2-phenylacetate 16.4 mmol, 4.22 g), was dissolved (in DMF(5 ml, 21.32 mmol) and the solution was cooled down to −15 C.°, then(3-(bis(trimethylsilyl)-amino)phenyl)magnesium chloride (21.32 ml, 21.32mmol) was added dropwise and the mixture left to reach rt. Methyl2-oxo-2-phenylacetate (3.5 g, 21.32 mmol) was dissolved in DMF dry (10ml) under argon and the solution was cooled down to −20 C.°, then(3-(bis(trimethylsilyl)amino)phenyl)magnesium chloride 1.0M in THF(21.32 ml, 21.32 mmol) was added dropwise and the mixture left to reachrt and stirred for further 1.5 h. The reaction was quenched by theaddition of Acetonitrile (20 ml) and partitioned between AcOEt (80 ml)and water (80 ml). Organic layer was washed twice with water, once withsat NaCl, dried over Na₂SO4 and dried under reduced pressure. The crudewas purified by flash chromatography on silica gel (eluent—from 95/5Hexane/AcOEt to 100% AcOEt) to afford the title compound (3.73 g, 14.50mmol, 68% yield).

UPLC-MS: 0.89 min, 258.1 [(M+H)]+, method 4.

Step 2; (R)-tert-butyl(2-(8-(benzyloxy)-2-oxo-1,2-dihydroquinolin-5-yl)-2-((tert-butyldimethylsilyl)oxy)ethyl)(5-hydroxypentyl)carbamate

(R)-8-(benzyloxy)-5-(2-bromo-1-((tert-butyldimethylsilyl)oxy)ethyl)quinolin-2(1H)-one(500 mg, 1.024 mmol) and 5-aminopentan-1-ol (106 mg, 1.024 mmol) weredissolved in NMP (3 ml) and the solution was stirred under nitrogen at85° C. overnight. The reaction mixture was partitioned between AcOEt andwater, the organic phase washed twice with water and the organic layerswere dried over Na2SO4 and evaporated under reduced pressure to give acrude that was dissolved in 1/1 THF and NaHCO3 sat. sol. (6 ml),ditertbutyldicarbonate (67.1 mg, 0.308 mmol) was added and the mixtureheated at rt for 1 h. The reaction mixture was partitioned between AcOEt(20 ml) and water and the organic phase washed twice with water, oncewith HCl 0.5M (20 ml) and once with brine. Organic layers were driedover Na₂SO4 and dried under reduced pressure. The crude was purified byflash chromatography on silica gel (eluent—from 100% Hexane to 20%/80%Hexane/Ethyl acetate 80%.) to give the title compound (76 mg, 0.124mmol, 12.16% yield).

UPLC-MS: 2.86 min, 611 [(M+H)]+, method 4.

Step 3; methyl2-(3-(((R)-10-(8-(benzyloxy)-2-oxo-1,2-dihydroquinolin-5-yl)-8-(tert-butoxycarbonyl)-12,12,13,13-tetramethyl-2,11-dioxa-8-aza-12-silatetradecan-1-oyl)amino)phenyl)-2-hydroxy-2-phenylacetate

Methyl 2-(3-aminophenyl)-2-hydroxy-2-phenylacetate (1 g, 3.89 mmol) wasdissolved in Acetonitrile (12 ml) and trichloromethyl carbonochloridate(1.922 g, 9.72 mmol) was added. The solution was stirred at rt for 7hours then it was evaporated under vacuum, added with 1 ml of DCM andevaporated again. The residue was dissolved in DCM (5 ml), added with(R)-tert-butyl(2-(8-(benzyloxy)-2-oxo-1,2-dihydroquinolin-5-yl)-2-((tert-butyldimethylsilyl)oxy)ethyl)(5-hydroxypentyl)carbamate(2.374 g, 3.89 mmol), and the reaction was stirred at rt for 6 hours.The solvent was evaporated and the residue purified by flashchromatography on silica gel (eluent—Hexane/Ethyl acetate from 0 to 90%)to afford the title compound (344 mg, 9.9%).

UPLC-MS: 1.64 min, 895.4 [(M+H)]+, method 2.

Step 4;2-(3-(((R)-10-(8-(benzyloxy)-2-oxo-1,2-dihydroquinolin-5-yl)-8-(tert-butoxycarbonyl)-12,12,13,13-tetramethyl-2,11-dioxa-8-aza-12-silatetradecan-1-oyl)amino)phenyl)-2-hydroxy-2-phenylaceticacid

Methyl2-(3-(((R)-10-(8-(benzyloxy)-2-oxo-1,2-dihydroquinolin-5-yl)-8-(tert-butoxycarbonyl)-12,12,13,13-tetramethyl-2,11-dioxa-8-aza-12-silatetradecan-1-oyl)amino)phenyl)-2-hydroxy-2-phenylacetate(143 mg, 0.160 mmol) was dissolved in DMF (0.7 ml) and LiOH 1N (0.320ml, 0.320 mmol) was dropped inside; the mixture was stirred at rt for 2h. The pH of mixture was adjust with a 1N HCl aq solution till pH=5.Reaction mixture was partitioned between AcOEt (5 ml) and water and theorganic phase washed twice with water then with brine. Finally theorganic solution was dried over sodium sulphate, evaporated under vacuumto afford the title compound (120 mg, 85%), that was used as such forthe next steps.

UPLC-MS: 1.59 min, 880.2 [(M+H)]+, method 2.

Step 5; (1-benzylpiperidin-4-yl)methyl2-(3-(((R)-8-(tert-butoxycarbonyl)-10-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)-12,12,13,13-tetramethyl-2,11-dioxa-8-aza-12-silatetradecan-1-oyl)amino)phenyl)-2-hydroxy-2-phenylacetate

2-(3-(((R)-10-(8-(benzyloxy)-2-oxo-1,2-dihydroquinolin-5-yl)-8-(tert-butoxy-carbonyl)-12,12,13,13-tetramethyl-2,11-dioxa-8-aza-12-silatetradecan-1-oyl)amino)-phenyl)-2-hydroxy-2-phenylaceticacid (120 mg, 0.136 mmol) was dissolved in DMF (1.5 ml, 0.136 mmol) anddi(1H-imidazol-1-yl)methanone, CDI (33.2 mg, 0.205 mmol) was added andthe mixture was stirred at rt for 1 h. Finally,(1-benzylpiperidin-4-yl)methanol (33.6 mg, 0.164 mmol) was added and thereaction was left to stir at rt for 3 h. Reaction mixture waspartitioned between AcOEt (20 ml) and water; the organic phase waswashed twice with water, HCl 0.5M (20 ml) and brine. Finally thesolution was dried over sodium sulphate and evaporated under vacuum. Theresidue was submitted to flash chromatography on silica gel (eluent—from100% AcOEt to 80/20 AcOEt/(NH₃ 7N in MeOH) to afford the title compound(75 mg, 0.070 mmol, 51.5% yield) as yellowish foam.

UPLC-MS: 2.51 min, 1066.6 [(M+H)]+, method 4.

Step 6; (1-benzylpiperidin-4-yl)methyl2-(3-(((R)-8-(tert-butoxycarbonyl)-10-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)-12,12,13,13-tetramethyl-2,11-dioxa-8-aza-12-silatetradecan-1-oyl)amino)phenyl)-2-hydroxy-2-phenylacetate

(1-benzylpiperidin-4-yl)methyl2-(3-(((R)-10-(8-(benzyloxy)-2-oxo-1,2-dihydroquinolin-5-yl)-8-(tert-butoxycarbonyl)-12,12,13,13-tetramethyl-2,11-dioxa-8-aza-12-silatetradecan-1-oyl)amino)phenyl)-2-hydroxy-2-phenylacetate(150 mg, 0.281 mmol) was dissolved in methanol (2 ml, 0.281 mmol) undernitrogen then the suspension was added with Pd/BaSO₄ (40 mg, 0.281 mmol)and hydrogenated for 2 h at rt under balloon pressure of hydrogen.Reaction mixture was filtered and dried to give the crude title compound(75 mg, 0.153 mmol, 54.6% yield) as a yellowish oil, used as is in thenext step without further purification.

UPLC-MS: 2.59 min, 977.53 [(M+H)]+, method 4.

Step 7; (Compound 54)

(1-benzylpiperidin-4-yl)methyl2-(3-(((R)-8-(tert-butoxycarbonyl)-10-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)-12,12,13,13-tetramethyl-2,11-dioxa-8-aza-12-silatetradecan-1-oyl)amino)phenyl)-2-hydroxy-2-phenylacetate(30 mg, 0.031 mmol) was dissolved in HCl 37% (0.5 ml) and the solutionwas stirred at room temperature for 5 min. with complete disappearing ofstarting material in UPLC. Evaporation of solvent was performed usingV10 Biotage. The residue was triturated in acetone and filtrate on acartridge to afford the title compound (54) (11 mg, 47%).

N R_(t) (min) [M + H]+ Method NMR data (400 MHz) Salt 2 eq unless stated54 4.19 763.1 5 (DMSO-d6) δ ppm 10.44 (br. s., 2 H), 9.58 (s, 1 H), 9.16(br. HCl s., 1 H), 8.66 (br. s., 1 H), 8.26 (d, J = 9.87 Hz, 1 H),7.69-6.82 (m, 15 H), 6.55 (d, J = 9.87 Hz, 1 H), 6.26-5.95 (m, 1 H),5.44 (dd, J = 10.03, 2.14 Hz, 1 H), 4.22 (d, J = 4.93 Hz, 2 H),4.06-3.87 (m, 4 H), 3.28 (d, J = 11.84 Hz, 2 H), 3.12-2.73 (m, 6 H),1.86-1.25 (m, 10 H)

Example 18. (R)-quinuclidin-3-yl2-hydroxy-2-(3-(5-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)pentanamido)phenyl)-2-phenylacetatebis hydrochloride (Compound 55)

Step 1; Methyl2-(3-(5-(((R)-2-(8-(benzyloxy)-2-oxo-1,2-dihydroquinolin-5-yl)-2-((tert-butyldimethylsilyl)oxy)ethyl)amino)pentanamido)phenyl)-2-hydroxy-2-phenylacetate

Methyl 2-(3-aminophenyl)-2-hydroxy-2-phenylacetate (500 mg, 1.943 mmol)obtained as in Example 17, step 1, was dissolved in DCM (2 ml) and5-bromopentanoyl chloride (504 mg, 2.53 mmol) was added and the reactionwas stirred at rt for 2 hours. The mixture was diluted with DCM (2 ml)and the organic phase was washed with NaHCO₃ saturated solution, thenwith 1M HCl and the twice with brine. The solution was dried over sodiumsulphate and evaporated under vacuum to give the title compound as apale brown oil (490 mg, 60%).

UPLC-MS: 1.82 min, 404.01 [(M+H)−H2O]+, method 4.

Step 2; Methyl2-(3-(5-(((R)-2-(8-(benzyloxy)-2-oxo-1,2-dihydroquinolin-5-yl)-2-((tert-butyldimethylsilyl)oxy)ethyl)amino)pentanamido)phenyl)-2-hydroxy-2-phenylacetate

(R)-5-(2-amino-1-((tert-butyldimethylsilyl)oxy)ethyl)-8-(benzyloxy)quinolin-2(1H)-one(376 mg, 0.885 mmol) was dissolved in DMF dry (2 ml). 4-aminobutan-1-ol(0.082 ml, 0.884 mmol) was added and the solution stirred under nitrogenat 95° C. for 4 hrs. Reaction mixture was partitioned between AcOEt andwater and the organic phase washed twice with water. The organic layerwas dried over Na₂SO₄ and evaporated under reduced pressure to give anpale yellow oil. The residue was purified by reversed phase flash columnchromatography (eluent—from 100% A to 100% B in 15CV; A: water/MeCN95/5+0.01% HCOOH; B: water/MeCN 5/95+0.01% HCOOH) to afford the titlecompound (464 mg, 0.607 mmol, 82% yield).

UPLC-MS: 2.13 min, 764.01 [(M+H)]+, method 4.

Step 3; Methyl2-(3-(5-(((R)-2-(8-(benzyloxy)-2-oxo-1,2-dihydroquinolin-5-yl)-2-((tert-butyldimethylsilyl)oxy)ethyl)(tert-butoxycarbonyl)amino)pentanamido)phenyl)-2-hydroxy-2-phenylacetate

Methyl2-(3-(5-(((R)-2-(8-(benzyloxy)-2-oxo-1,2-dihydroquinolin-5-yl)-2-((tert-butyldimethylsilyl)oxy)ethyl)amino)pentanamido)phenyl)-2-hydroxy-2-phenylacetate(170 mg, 0.223 mmol) was dissolved in THF (1 ml), the di-tert-butyldicarbonate (72.8 mg, 0.334 mmol) and NaHCO3 saturated solution (1 ml,4.45 mmol) were added and the mixture was stirred at rt for 1 h.Reaction mixture was partitioned between AcOEt (20 ml) and water and theorganic phase washed twice with water, HCl 0.5M (20 ml) and brine.Finally the organic solution was dried over sodium sulphate, evaporatedunder vacuum to give the title compound in quantitative yield (192 mg).No purification was needed.

UPLC-MS: 1.57 min, 864.37 [(M+H)]+, method 2.

Step 4;2-(3-(5-(((R)-2-(8-(benzyloxy)-2-oxo-1,2-dihydroquinolin-5-yl)-2-((tert-butyldimethylsilyl)oxy)ethyl)(tert-butoxycarbonyl)amino)pentanamido)phenyl)-2-hydroxy-2-phenylaceticacid

Methyl2-(3-(5-(((R)-2-(8-(benzyloxy)-2-oxo-1,2-dihydroquinolin-5-yl)-2-((tert-butyldimethylsilyl)oxy)ethyl)(tert-butoxycarbonyl)amino)pentanamido)phenyl)-2-hydroxy-2-phenylacetate(170 mg, 0.197 mmol) was dissolved in DMF (1 ml) and LiOH 1N (0.393 ml,0.393 mmol) was added and the mixture was stirred at rt for 1 h. The pHof mixture was adjust with a 1N HCl aq solution till pH=5. Reactionmixture was partitioned between AcOEt (5 ml) and water and the organicphase washed twice with water then with brine. Finally the organicsolution was dried over sodium sulphate, evaporated under vacuum toafford the title compound (170 mg, 90%). No purification was needed.

UPLC-MS: 1.50 min, 850.01 [(M+H)]+, method 2.

Step 5; (R)-quinuclidin-3-yl2-(3-(5-(((R)-2-(8-(benzyloxy)-2-oxo-1,2-dihydroquinolin-5-yl)-2-((tert-butyldimethylsilyl)oxy)ethyl)(tert-butoxycarbonyl)amino)pentanamido)-phenyl)-2-hydroxy-2-phenylacetate

2-(3-(5-(((R)-2-(8-(benzyloxy)-2-oxo-1,2-dihydroquinolin-5-yl)-2-((tert-butyldimethylsilyl)oxy)ethyl)(tert-butoxycarbonyl)amino)pentanamido)phenyl)-2-hydroxy-2-phenylaceticacid (170 mg, 0.20 mmol) was dissolved in DMF (1.3 ml) anddi(1H-imidazol-1-yl)methanone, CDI (48.6 mg, 0.30 mmol) was added andthe mixture was stirred at rt for 1 h. Finally (R)-quinuclidin-3-ol(30.5 mg, 0.240 mmol) was added and the reaction was left to stir at rtfor 3 h. Reaction mixture was partitioned between AcOEt (20 ml) andwater; the organic phase was washed twice with water, HCl 0.5M (20 ml)and brine. Finally the solution was dried over sodium sulphate andevaporated under vacuum. The residue was purified by flash columnchromatography (eluent—100% AcOEt to 80/20 AcOEt/NH3 7N in MeOH) toafford the title compound (105 mg, 54.7%).

UPLC-MS: 1.30 min, 959.52 [(M+H)]+, method 2.

Step 6; (R)-quinuclidin-3-yl2-(3-(5-((tert-butoxycarbonyl)((R)-2-((tert-butyldimethyl-silyl)oxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)pentanamido)-phenyl)-2-hydroxy-2-phenylacetate

(1-benzylpiperidin-4-yl)methyl2-(3-(((R)-10-(8-(benzyloxy)-2-oxo-1,2-dihydroquinolin-5-yl)-8-(tert-butoxycarbonyl)-12,12,13,13-tetramethyl-2,11-dioxa-8-aza-12-silatetradecan-1-oyl)amino)phenyl)-2-hydroxy-2-phenylacetate(102 mg, 0.106 mmol) was dissolved in Methanol (1.5 ml) under nitrogenthen the suspension was added with Pd/BaSO4 (40 mg, 0.281 mmol) andhydrogenated for 2 h at rt under balloon pressure of hydrogen. Reactionmixture was filtered and dried to give the crude(1-benzylpiperidin-4-yl)methyl2-(3-(((R)-8-(tert-butoxycarbonyl)-10-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)-12,12,13,13-tetramethyl-2,11-dioxa-8-aza-12-silatetradecan-1-oyl)amino)phenyl)-2-hydroxy-2-phenylacetate(75 mg, 0.086 mmol, 81.1% yield) as a yellowish oil, used as is in thenext step without further purification.

UPLC-MS: 2.29 min, 435.1 [(M+H)/2]+, method 4.

Step 7; (Compound 55)

(R)-quinuclidin-3-yl2-(3-(5-((tert-butoxycarbonyl)((R)-2-((tert-butyldimethyl-silyl)oxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)pentanamido)-phenyl)-2-hydroxy-2-phenylacetate(45 mg, 0.052 mmol) was dissolved in HCl 35% (0.7 ml) and stirred at rtfor 5 min. with complete disappearing of starting material in UPLC.Evaporation of solvent was performed using V10 Biotage. The residue wastriturated in acetone and filtrate on a cartridge to afford the titlecompound (55) (34 mg, 88%).

N R_(t) (min) [M + H]+ Method NMR data (400 MHz) Salt 2 eq unless stated55 3.38/3.41 655.1 5 1H NMR (400 MHz, DMSO-d6) δ ppm 10.60-10.37 (3 s,HCl 3 H each), 9.94-5.17 (m, 21 H), 5.21-5.08 (m, 1 H), 3.75-1.75 (m, 17H);

Example 19. (1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-(3-(3-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzamido)-propyl)ureido)phenyl)-2-phenylacetatediformate (Compound 56)

Step 1; methyl2-(3-(3-(3-((tert-butoxycarbonyl)amino)propyl)ureido)phenyl)-2-hydroxy-2-phenylacetate

Methyl 2-(3-aminophenyl)-2-hydroxy-2-phenylacetate (500 mg, 1.943 mmol)obtained as in Example 17, step 1, was dissolved in acetonitrile (1.5ml, 1.943 mmol) and trichloromethyl carbonochloridate (961 mg, 4.86mmol) was added. The solution was stirred at rt for 7 hours then it wasevaporated under vacuum, added with 1 ml of DCM and evaporated again.The residue was dissolved in DCM (3 ml) and added with tert-butyl(3-aminopropyl)carbamate (Aldrich, 339 mg, 1.943 mmol). The reaction wasstirred at rt 1 hour, just after a few minutes abundant precipitation ofsalt. The solvent was filtered and the filtrate was evaporated to give apale yellow oil of title compound (800 mg, 1.749 mmol, 90%). No furtherpurification was needed.

UPLC-MS: 1.15 min, 457.1 ([M+H]+), method 2.

Step 2;2-(3-(3-(3-((tert-butoxycarbonyl)amino)propyl)ureido)phenyl)-2-hydroxy-2-phenylaceticacid

Methyl2-(3-(3-(3-((tert-butoxycarbonyl)amino)propyl)ureido)phenyl)-2-hydroxy-2-phenylacetate(200 mg, 0.437 mmol) and LiOH (52.3 mg, 2.186 mmol) were dissolved intetrahydrofuran (Volume: 1.5)/Water (Volume: 1.5) for 2 h at rt, thenthe mixture partitioned between AcOEt and HCl 0.2M. Organic layer waswashed with sat NaCl aq, dried over Na2SO4 dry and evaporated underreduced pressure to give2-(3-(3-(3-((tert-butoxycarbonyl)amino)propyl)ureido)phenyl)-2-hydroxy-2-phenylaceticacid (174 mg, 0.393 mmol, 90% yield) as a white foam. No furtherpurification was needed.

UPLC-MS: 0.93 min, 444.1 [M+H]+, method 2.

Step 3; (1-benzylpiperidin-4-yl)methyl2-(3-(3-(3-aminopropyl)ureido)phenyl)-2-hydroxy-2-phenylacetate

2-(3-(3-(3-((tert-butoxycarbonyl)amino)propyl)ureido)phenyl)-2-hydroxy-2-phenylaceticacid (200 mg, 0.451 mmol) were reacted withdi(1H-imidazol-1-yl)methanone (146 mg, 0.902 mmol) for 30 min. at rt,then (1-benzylpiperidin-4-yl)methanol (278 mg, 1.353 mmol) was added andthe reaction stirred for 2 h at 60° C., then at rt overnight. The crudewas partitioned between sat NaHCO3 and AcOEt. Organic layer was driedover Na2SO4 and dried under reduced pressure. The crude was purifiedover silica gel by flash chromatography (silica gel, eluents: from 100%AcOEt to 80/20 AcOEt/NH3 7N in MeOH) to afford the title compound (138mg, 0.219 mmol, 48.5% yield)

UPLC-MS: 1.29 min, 630.55 [M+H]+, method 4.

Step 4; (1-benzylpiperidin-4-yl)methyl2-(3-(3-(3-aminopropyl)ureido)phenyl)-2-hydroxy-2-phenylacetate bishydrochloride

(1-benzylpiperidin-4-yl)methyl2-(3-(3-(3-((tert-butoxycarbonyl)amino)propyl)-ureido)phenyl)-2-hydroxy-2-phenylacetate(138 mg, 0.219 mmol) was stirred for 1 h at rt in Dioxane/HCl 4N (1.5ml) diluted with further 1.5 mL of dioxane; then the mixture was driedunder reduce pressure and the residue triturated in Et₂O to give(1-benzylpiperidin-4-yl)methyl2-(3-((3-aminopropyl)carbamoyl)phenyl)-2-hydroxy-2-phenylacetate, 2HCl(0.22 g, 0.374 mmol, 74.2% yield) and (1-benzylpiperidin-4-yl)methyl2-(3-((3-aminopropyl)carbamoyl)phenyl)-2-hydroxy-2-phenylacetate (0.090g, 0.170 mmol, 77.6% yield) both as white solid used in the next stepswithout further purifications.

UPLC-MS: 0.51 min, 530.86 [M+H]+, method 4.

Step 5; (1-benzylpiperidin-4-yl)methyl2-(3-(3-(3-(4-(((tert-butoxycarbonyl)((R)-2-((tert-butyldimethylsilyl)oxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)-methyl)benzamido)propyl)ureido)phenyl)-2-hydroxy-2-phenylacetate

(R)-4-(((tert-butoxycarbonyl)(2-((tert-butyldimethylsilyl)oxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzoicacid, obtained as described in Procedure 4, steps 1-5 (65.2 mg, 0.115mmol) and TBTU (36.6 mg, 0.115 mmol) were reacted for 5 min in 1.1 mL ofDMF, then (1-benzylpiperidin-4-yl)methyl2-(3-(3-(3-aminopropyl)ureido)phenyl)-2-hydroxy-2-phenylacetate (90 mg,0.149 mmol) and DIEA (58.0 μl, 0.332 mmol) were added and the mixturestirred for 1 h at 60° C. Reaction was partitioned between AcOEt andsaturated NaHCO₃, organic layer was washed twice with water, saturatedNaCl aq, then dried over Na₂SO₄ and evaporated to dryness. The orangeresulting oil (43.4 mg, 0.040 mmol, 35% yield) was used in the next stepwithout further purifications.

UPLC-MS: 1.14 min, 1081.24 [M+H]+, method 2.

Step 6; (Compound 56)

(1-benzylpiperidin-4-yl)methyl2-(3-(3-(3-(4-(((tert-butoxycarbonyl)((R)-2-((tert-butyldimethylsilyl)oxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)-methyl)benzamido)propyl)ureido)phenyl)-2-hydroxy-2-phenylacetate(50 mg, 0.046 mmol) was dissolved in acetonitrile (1 ml) and HCl 5N (1ml) were added. The mixture was stirred at rt for 15 min. then submittedto reverse phase flash chromatography (C18 silica gel, eluents: from100% A to 100% B, A: water/MeCN 95/5+0.1% HCOOH, B: MeCN/water 95/5+0.1%HCOOH) to afford the title compound (56) (17 mg, 0.020 mmol, 43.5%yield).

N R_(t) (min) [M + H]+ Method NMR data (400 MHz) Salt 2 eq unless stated56 3.94 867.0 5 ¹H NMR (400 MHz, DMSO-d6) δ ppm Formate 10.45-10.11 (m,2 H), 8.60-6.12 (m, 36 H), 3.78-0.82 (m, 18 H)

Example 20

(1-Benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-((2-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzamido)ethyl)amino)-2-oxoethoxy)phenyl)-2-phenylacetate(Compound 57)

Step 1; (1-Benzylpiperidin-4-yl)methyl(S)-2-(3-(2-((2-((tert-butoxycarbonyl)-amino)ethyl)amino)-2-oxoethoxy)phenyl)-2-hydroxy-2-phenylacetate

To a stirred solution of(S)-2-(3-(2-((1-benzylpiperidin-4-yl)methoxy)-1-hydroxy-2-oxo-1-phenylethyl)phenoxy)aceticacid hydrochloride (0.20 g, 0.38 mmol) in DMF (1.9 mL) was added DIPEA(0.132 mL, 0.76 mmol) and HATU (0.173 g, 0.46 mmol) and the mixturestirred at room temperature for 30 minutes. To this mixture was added asolution of N-(tert-butoxycarbonyl)ethylenediamine HCl (0.061 g, 0.38mmol) and DIPEA (0.13 mL, 0.76 mmol) in DMF (1.9 mL). The reactionmixture diluted with ethyl acetate and washed with 2M aqueous sodiumhydroxide and brine. The organic phase was dried over magnesium sulfate,filtered and the filtrate evaporated at reduced pressure to afford thetitle compound (0.265 g, >100%).

¹H NMR (400 MHz, CDCl₃); δ 7.39 (dd, J=1.9, 7.7 Hz, 2H), 7.34-7.17 (m,10H), 7.07-7.04 (m, 2H), 6.87 (dd, J=2.0, 7.9 Hz, 1H), 5.07 (s, 1H),4.42 (s, 2H), 4.14-4.07 (m, 4H), 3.48 (s, 2H), 3.42-3.38 (m, 3H),3.29-3.22 (m, 2H), 2.97 (s, 2H), 2.85-2.81 (m, 2H), 1.96-1.88 (m, 2H),1.67-1.56 (m, 1H), 1.40 (s, 9H).

Step 2; (1-Benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-((2-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzamido)ethyl)-amino)-2-oxoethoxy)phenyl)-2-phenylacetate(Compound 57)

To a stirred solution of (1-benzylpiperidin-4-yl)methyl(S)-2-(3-(2-((2-((tert-butoxycarbonyl)amino)ethyl)amino)-2-oxoethoxy)phenyl)-2-hydroxy-2-phenylacetate(0.265 g, 0.42 mmol) was added a solution of HCl in dioxan (4M, 15 mL)and the mixture stirred at room temperature for 1 hour. The solventevaporated under reduced pressure. The residue was dissolved in DMF (3ml) and added to a pre-stirred (15 minutes) mixture of(R)-4-(((tert-butoxycarbonyl)(2-((tert-butyldimethylsilyl)oxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzoicacid (0.20 g, 0.35 mmol), DIPEA (0.214 mL, 1.23 mmol) and HATU (0.16 g,0.42 mmol) in DMF (2 mL). The reaction mixture was stirred at roomtemperature for 18 hours. The reaction mixture dissolved in ethylacetate and washed with saturated aqueous sodium carbonate and brine.The organic phase was dried with magnesium sulfate, filtered and thefiltrate evaporated at reduced pressure. The residue was dissolved indioxan (1 mL) and a solution of HCl—dioxan (2 mL) added. The reactionmixture was stirred at room temperature for 1 hour. The solvent wasevaporated at reduced pressure and the residue purified by reversepreparative HPLC.

¹H NMR (400 MHz, DMSO-d₆); δ 10.50 (s, 2H), 9.44 (s, 1H), 9.16 (s, 2H),8.61 (dd, J=5.3, 5.3 Hz, 1H), 8.30 (dd, J=5, 4, 5.4 Hz, 1H), 8.08 (d,J=9.9 Hz, 1H), 7.88 (d, J=8.3 Hz, 2H), 7.61 (d, J=8.4 Hz, 2H), 7.47 (s,5H), 7.33 (d, J=4.5 Hz, 3H), 7.32-7.23 (m, 3H), 7.12 (d, J=8.3 Hz, 1H),7.00-6.93 (m, 2H), 6.89 (dd, J=2.3, 8.0 Hz, 2H), 6.67 (s, 1H), 6.57 (d,J=9.9 Hz, 1H), 6.19 (s, 1H), 5.36-5.32 (m, 1H), 4.43 (s, 2H), 4.30-4.23(m, 4H), 4.01 (d, J=5.0 Hz, 2H), 3.36-3.28 (m, 5H), 3.09-3.08 (m, 2H),3.04-2.94 (m, 1H), 2.93-2.88 (m, 2H), 1.78-1.66 (m, 3H), 1.40-1.31 (m,2H).

The following compounds were prepared in a similar fashion using theappropriate amine:

N Appropriate amine Structure 58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

(Salt 2 eq N Rt (min) Method NMR data (400 MHz) unless stated) 57 2.3811 (DMSO-d₆); δ 10.50 (s, 2H), 9.44 (s, 1H), 9.16 (s, 2H), 8.61 (dd, J =5.3, 5.3 Hz, 1H), TFA 8.30 (dd, J = 5.4, 5.4 Hz, 1H), 8.08 (d, J = 9.9Hz, 1H), 7.88 (d, J = 8.3 Hz, 2H), 7.61 (d, J = 8.4 Hz, 2H), 7.47 (s,5H), 7.33 (d, J = 4.5 Hz, 3H), 7.32-7.23 (m, 3H), 7.12 (d, J = 8.3 Hz,1H), 7.00-6.93 (m, 2H), 6.89 (dd, J = 2.3, 8.0 Hz, 2H), 6.67 (s, 1H),6.57 (d, J = 9.9 Hz, 1H), 6.19 (s, 1H), 5.36-5.32 (m, 1H), 4.43 (s, 2H),4.30-4.23 (m, 4H), 4.01 (d, J = 5.0 Hz, 2H), 3.36-3.28 (m, 5H),3.09-3.08 (m, 2H), 3.04-2.94 (m, 1H), 2.93-2.88 (m, 2H), 1.78-1.66 (m,3H), 1.40-1.31 (m, 2H). 58 2.43 11 (DMSO-d₆); δ 10.52 (s, 2H), 9.40 (s,1H), 9.12-9.12 (m, 2H), 8.07 (d, J = 9.9 Hz, TFA 1H), 7.62 (d, J = 8.3Hz, 2H), 7.51 (d, J = 8.3 Hz, 2H), 7.47 (s, 6H), 7.33 (d, J = 4.4 Hz,4H), 7.31-7.21 (m, 2H), 7.15-7.11 (m, 1H), 6.98 (d, J = 8.2 Hz, 1H),6.93-6.88 (m, 3H), 6.58 (d, J = 9.7 Hz, 1H), 6.20 (s, 1H), 5.35 (dd, J =2.1, 9.9 Hz, 1H), 4.82 (s, 2H), 4.29-4.21 (m, 6H), 4.04-3.97 (m, 5H),3.34 (d, J = 12.1 Hz, 4H), 3.12-2.98 (m, 3H), 2.92-2.88 (m, 2H),1.77-1.67 (m, 3H), 1.41-1.33 (m, 2H). 59 2.45 11 (DMSO-d₆); δ 8.24 (d, J= 7.7 Hz, 1H), 8.12 (d, J = 9.9 Hz, 1H), 7.79 (d, J = 8.3 Hz, Free Base2H), 7.38 (d, J = 8.3 Hz, 2H), 7.32 (d, J = 4.4 Hz, 4H), 7.30-7.21 (m,7H), 7.06 (d, J = 8.2 Hz, 1H), 6.91 (d, J = 7.8 Hz, 3H), 6.85 (dd, J =1.9, 7.3 Hz, 1H), 6.61 (s, 1H), 6.46 (d, J = 9.9 Hz, 1H), 5.36 (s, 1H),5.06 (dd, J = 4.1, 7.8 Hz, 1H), 4.80-4.71 (m, 2H), 4.28 (d, J = 12.5 Hz,1H), 4.04 (dd, J = 3.2, 7.2 Hz, 1H), 4.00 (d, J = 6.3 Hz, 2H), 3.85-3.81(m, 1H), 3.79 (s, 2H), 3.13 (dd, J = 11.7, 11.7 Hz, 1H), 2.76-2.59 (m,5H), 1.86-1.77 (m, 4H), 1.54-1.44 (m, 6H), 1.15-1.06 (m, 2H). 60 2.39 11(DMSO-d₆); δ 10.33 (s, 1H), 8.65 and 8.46 (s, 1H), 8.12 (dd, J = 4.6,10.0 Hz, 1H), Free Base 7.77 (dd, J = 8.3, 10.3 Hz, 2H), 7.40 (dd, J =5.7, 7.8 Hz, 2H), 7.34-7.23 (m, 9H), 7.14 (dd, J = 8.0, 8.0 Hz, 1H),7.05 (dd, J = 8.4, 8.4 Hz, 2H), 6.92-6.78 (m, 3H), 6.68-6.57 (m, 1H),6.47 (d, J = 9.8 Hz, 1H), 5.41 (s, 1H), 5.10-5.06 (m, 1H), 4.74 (d, J =12.4 Hz, 2H), 4.01-3.96 (m, 2H), 3.81 (s, 2H), 3.46 (s, 2H), 3.38 (s,3H), 3.00 (s, 2H), 2.85 (s, 2H), 2.74-2.66 (m, 5H), 1.85-1.79 (m, 2H),1.51-1.44 (m, 2H), 1.15-1.06 (m, 2H). 61 2.50 11 (DMSO-d₆); δ 10.51 (s,1H), 10.49 (s, 1H), 9.40 (s, 1H), 9.15 (s, 2H), 8.58 (dd, J = 5.7, TFA5.7 Hz, 1H), 8.07 (d, J = 7.9 Hz, 1H), 7.91 (d, J = 8.0 Hz, 2H), 7.62(d, J = 8.4 Hz, 2H), 7.46 (s, 5H), 7.34-7.32 (m, 3H), 7.32-7.29 (m, 1H),7.23 (dd, J = 8.0, 8.0 Hz, 1H), 7.12 (d, J = 8.2 Hz, 1H), 6.97 (d, J =8.2 Hz, 1H), 6.90 (d, J = 7.9 Hz, 1H), 6.86 (s, 1H), 6.83 (d, J = 8.3Hz, 1H), 6.63 (s, 1H), 6.58-6.53 (m, 2H), 6.19 (d, J = 2.5 Hz, 1H),5.37-5.36 (m, 1H), 4.75 (d, J = 3.5 Hz, 2H), 4.29-4.28 (m, 6H), 4.02 (d,J = 6.1 Hz, 2H), 3.83-3.83 (m, 1H), 3.15-3.14 (m, 5H), 3.02 (s, 4H),1.82-1.81 (m, 1H), 1.71 (s, 6H), 1.35-1.35 (m, 3H). 62 2.50 11(DMSO-d₆); δ 10.51 (s, 1H), 10.47 (s, 1H), 9.38 (s, 1H), 9.13 (s, 2H),8.29 (d, J = 7.8 Hz, TFA 1H), 8.07 (d, J = 10.1 Hz, 1H), 7.96 (d, J =8.0 Hz, 1H), 7.89 (d, J = 8.3 Hz, 2H), 7.60 (d, J = 8.4 Hz, 2H), 7.48(m, 5H), 7.34-7.32 (m, 6H), 7.12 (d, J = 8.3 Hz, 1H), 7.00-6.93 (m, 3H),6.88 (dd, J = 2.4, 8.2 Hz, 1H), 6.66 (s, 1H), 6.57 (dd, J = 2.1, 9.9 Hz,1H), 6.19-6.19 (m, 1H), 5.33 (d, J = 10.0 Hz, 1H), 4.41 (s, 2H),4.31-4.21 (m, 4H), 4.04-3.97 (m, 2H), 3.75-3.74 (m, 1H), 3.61-3.61 (m,1H), 3.33 (d, J = 11.8 Hz, 2H), 3.09-3.08 (m, 2H), 3.01-2.87 (m, 3H),1.88-1.67 (m, 6H), 1.43-1.34 (m, 6H). 63 2.43 11 (DMSO-d₆); δ 10.51 (s,1H), 10.47 (s, 1H), 9.38 (s, 1H), 9.13 (s, 2H), 8.79 (d, J = 7.0 Hz, TFA1H), 8.51 (d, J = 7.4 Hz, 1H), 8.08 (d, J = 10.0 Hz, 1H), 7.93 (d, J =8.4 Hz, 2H), 7.62 (d, J = 8.3 Hz, 2H), 7.48 (s, 5H), 7.35-7.26 (m, 6H),7.12 (d, J = 8.3 Hz, 1H), 7.02-6.93 (m, 3H), 6.89 (dd, J = 2.6, 7.9 Hz,1H), 6.67-6.66 (m, 1H), 6.58 (d, J = 9.3 Hz, 1H), 6.19-6.19 (m, 1H),5.36-5.34 (m, 1H), 4.43 (s, 4H), 4.31-4.21 (m, 5H), 4.03 (d, J = 6.5 Hz,2H), 3.34 (d, J = 11.5 Hz, 2H), 3.11-2.87 (m, 3H), 2.35 (dd, J = 6.9,6.9 Hz, 4H), 1.77-1.67 (m, 3H), 1.40-1.31 (m, 2H). 64 2.46 11 (DMSO-d₆);δ 10.60 (s, 1H), 10.50 (s, 1H), 9.40 (s, 1H), 9.10 (s, 2H), 8.06 (d, TFAJ = 10.4 Hz, 1H), 7.60 (d, J = 8.2 Hz, 2H), 7.48 (s, 5H), 7.45 (d, J =8.2 Hz, 2H), 7.36-7.27 (m, 5H), 7.23 (t, J = 7.9 Hz, 1H), 7.13 (d, J =8.3 Hz, 1H), 6.98 (d, J = 8.2 Hz, 1H), 6.91-6.87 (m, 2H), 6.86-6.81 (m,1H), 6.64 (s, 1H), 6.59-6.55 (m, 1H), 6.15 (s, 1H), 5.35-5.33 (m, 1H),4.76 (s, 2H), 4.32-4.22 (m, 4H), 4.04-3.97 (m, 2H), 3.62 (s, 2H),3.44-3.26 (m, 8H), 3.10-3.02 (m, 3H), 2.95-2.86 (m, 2H), 1.76-1.66 (m,2H), 1.50 (s, 4H), 1.42-1.33 (m, 6H). 65 2.43 11 (DMSO-d₆); δ 10.55 (s,1H), 10.45 (s, 1H), 9.40 (s, 1H), 8.75 (s, 2H), 8.08 (d, J = 9.9 Hz, TFA1H), 8.04 (d, J = 7.4 Hz, 1H), 7.61 (d, J = 8.2 Hz, 2H), 7.47 (s, 5H),7.44 (d, J = 7.4 Hz, 2H), 7.32 (d, J = 4.4 Hz, 4H), 7.30-7.23 (m, 2H),7.13 (d, J = 8.3 Hz, 1H), 7.00-6.92 (m, 3H), 6.87 (dd, J = 2.3, 8.1 Hz,1H), 6.65 (s, 1H), 6.58 (d, J = 9.9 Hz, 1H), 6.15 (s, 1H), 5.35-5.33 (m,1H), 4.42 (s, 2H), 4.32-4.20 (m, 4H), 4.03-3.97 (m, 2H), 3.93-3.88 (m,1H), 3.48-3.48 (m, 1H), 3.34 (d, J = 11.9 Hz, 2H), 3.11-3.02 (m, 4H),2.94-2.86 (m, 3H), 1.85-1.84 (m, 1H), 1.76-1.66 (m, 4H), 1.39-1.30 (m,4H). 66 2.39 11 (MeOD); δ 8.29 (d, J = 9.8 Hz, 1H), 7.75 (d, J = 7.9 Hz,2H), 7.63 (d, J = 6.9 Hz, 2H), TFA 7.53-7.48 (m, 4H), 7.39 (d, J = 7.2Hz, 2H), 7.34-7.27 (m, 6H), 7.09 (s, 1H), 7.04 (d, J = 8.3 Hz, 2H), 6.98(dd, J = 2.2, 8.0 Hz, 1H), 6.66 (d, J = 9.3 Hz, 1H), 5.43 (dd, J = 6.7,6.7 Hz, 1H), 4.76-4.69 (m, 1H), 4.60 (dd, J = 7.9, 7.9 Hz, 1H), 4.52 (s,2H), 4.46 (dd, J = 9.1, 9.1 Hz, 1H), 4.28 (s, 3H), 4.12 (d, J = 6.4 Hz,3H), 3.51-3.45 (m, 2H), 3.27 (d, J = 6.7 Hz, 2H), 3.01-2.91 (m, 2H),2.68 (s, 3H), 1.83 (d, J = 14.1 Hz, 2H), 1.42 (d, J = 12.9 Hz, 2H). 672.42 11 (MeOD); δ 8.52 (s, 2H), 8.29 (d, J = 9.9 Hz, 1H), 7.91 (d, J =8.0 Hz, 2H), 7.56 (d, Formate J = 8.3 Hz, 2H), 7.42-7.38 (m, 6H),7.37-7.23 (m, 6H), 7.09-7.05 (m, 1H), 7.03-6.97 (m, 2H), 6.93 (dd, J =2.5, 8.2 Hz, 1H), 6.63 (d, J = 9.8 Hz, 1H), 5.35 (dd, J = 4.3, 8.8 Hz,1H), 4.84-4.76 (m, 1H), 4.70-4.59 (m, 3H), 4.41-4.27 (m, 2H), 4.18-4.10(m, 5H), 3.94 (d, J = 2.3 Hz, 2H), 3.22-3.04 (m, 4H), 2.56 (dd, J =12.4, 12.4 Hz, 2H), 1.85-1.79 (m, 1H), 1.71-1.64 (m, 2H), 1.43-1.30 (m,2H). 68 2.38 11 (DMSO-d₆, 100° C.) δ 8.12 (d, J = 9.8 Hz, 1H), 7.99 (d,J = 6.3 Hz, 1H), 7.58 (q, J = 8.6 Hz, TFA 4H), 7.50-7.47 (m, 5H),7.41-7.24 (m, 6H), 7.14 (d, J = 8.3 Hz, 1H), 7.04-7.00 (m, 3H), 6.90(dd, J = 2.2, 8.0 Hz, 1H), 6.56 (d, J = 9.9 Hz, 1H), 5.39 (dd, J = 4.6,8.3 Hz, 1H), 4.44 (s, 2H), 4.34-4.30 (m, 3H), 4.26 (s, 2H), 4.13-4.06(m, 2H), 3.76-3.70 (m, 2H), 3.37-3.29 (m, 4H), 3.23-3.15 (m, 2H),2.95-2.91 (m, 2H), 2.19-2.10 (m, 1H), 1.97-1.87 (m, 2H), 1.80-1.76 (m,2H), 1.49-1.49 (m, 2H). 69 2.46 11 (DMSO-d₆, 100° C.) δ 8.19-8.15 (m,3H), 7.57 (d, J = 7.5 Hz, 1H), 7.40-7.23 (m, Formate 15H), 7.10 (d, J =8.3 Hz, 1H), 7.06-7.00 (m, 2H), 6.96 (d, J = 8.2 Hz, 1H), 6.90 (dd, J =2.3, 8.0 Hz, 1H), 6.47 (d, J = 9.9 Hz, 1H), 5.09 (dd, J = 4.6, 7.7 Hz,1H), 4.41 (d, J = 2.8 Hz, 2H), 4.05 (d, J = 6.3 Hz, 2H), 3.92 (d, J =14.0 Hz, 1H), 3.81 (s, 2H), 3.72 (d, J = 13.4 Hz, 1H), 3.44 (s, 2H),3.13-3.02 (m, 3H), 2.88-2.67 (m, 4H), 1.97-1.86 (m, 3H), 1.71-1.49 (m,6H), 1.28-1.13 (m, 2H). 70 2.42 11 (DMSO-d₆, 100° C.) δ 8.19-8.15 (m,3H), 7.92 (d, J = 6.4 Hz, 1H), 7.45-7.23 (m, Formate 15H), 7.09 (d, J =8.0 Hz, 1H), 7.04-7.00 (m, 2H), 6.96 (d, J = 8.0 Hz, 1H), 6.90 (dd, J =2.4, 8.1 Hz, 1H), 6.47 (d, J = 9.9 Hz, 1H), 5.08 (dd, J = 4.7, 7.6 Hz,1H), 4.43 (s, 2H), 4.40-4.30 (m, 1H), 4.05 (d, J = 6.4 Hz, 2H), 3.82 (s,2H), 3.70 (dd, J = 6.7, 11.4 Hz, 1H), 3.62-3.47 (m, 2H), 3.45 (s, 2H),3.36 (dd, J = 5.3, 11.5 Hz, 1H), 2.88-2.71 (m, 4H), 2.20-2.07 (m, 1H),1.98-1.85 (m, 3H), 1.62-1.49 (m, 3H), 1.28-1.13 (m, 2H). 71 2.41 11(DMSO-d₆, 100° C.) δ 8.11 (d, J = 9.9 Hz, 1H), 7.66 (d, J = 7.7 Hz, 1H),7.60 (d, J = 8.2 Hz, TFA 2H), 7.46 (d, J = 8.5 Hz, 7H), 7.41-7.24 (m,6H), 7.14 (d, J = 8.2 Hz, 1H), 7.06-7.00 (m, 3H), 6.90 (dd, J = 2.3, 8.2Hz, 1H), 6.56 (d, J = 9.9 Hz, 1H), 5.38 (dd, J = 4.7, 8.2 Hz, 1H), 4.42(s, 2H), 4.31 (d, J = 2.4 Hz, 2H), 4.23 (s, 2H), 4.10 (d, J = 5.6 Hz,2H), 4.00-3.95 (m, 1H), 3.85-3.74 (m, 2H), 3.50-3.25 (m, 2H), 3.23-2.98(m, 5H), 2.57-2.53 (m, 1H), 1.92-1.87 (m, 2H), 1.81-1.71 (m, 3H),1.66-1.47 (m, 4H). 72 2.43 11 (DMSO-d₆, 100° C.) δ 8.19-8.12 (m, 2H),7.86 (d, J = 6.5 Hz, 1H), 7.78 (d, J = 8.0 Hz, mono-Formate 2H), 7.39(d, J = 7.9 Hz, 4H), 7.35-7.20 (m, 8H), 7.09 (d, J = 8.2 Hz, 1H),7.01-6.94 (m, 3H), 6.90-6.86 (m, 1H), 6.48 (d, J = 9.8 Hz, 1H), 5.11(dd, J = 4.6, 7.5 Hz, 1H), 4.72 (s, 2H), 4.04 (d, J = 6.4 Hz, 3H), 3.85(br s, 4H), 3.46 (s, 2H), 2.89-2.71 (m, 5H), 2.54-2.40 (m, 1H),2.06-1.92 (m, 3H), 1.81-1.77 (m, 1H), 1.69-1.57 (m, 2H), 1.52-1.50 (m,3H), 1.24-1.14 (m, 2H). 73 2.45 11 (DMSO-d₆, 100° C.) δ 8.17 (d, J = 7.9Hz, 3H), 7.79 (d, J = 8.3 Hz, 2H), 7.41-7.36 (m, mono-Formate 4H),7.35-7.21 (m, 9H), 7.09 (d, J = 8.2 Hz, 1H), 7.00-6.94 (m, 3H), 6.89(dd, J = 1.9, 8.2 Hz, 1H), 6.47 (d, J = 9.9 Hz, 1H), 5.08 (dd, J = 4.9,7.7 Hz, 1H), 4.64 (s, 2H), 4.54-4.45 (m, 1H), 4.05 (d, J = 6.3 Hz, 2H),3.85-3.21 (m, 3H), 3.65-3.59 (m, 1H), 3.46-3.43 (m, 3H), 2.87-2.67 (m,4H), 2.56-2.47 (m, 1H under the DMSO), 2.17-2.17 (m, 1H), 2.06-2.00 (m,1H), 1.98-1.90 (m, 2H), 1.62-1.49 (m, 3H), 1.25-1.13 (m, 2H). 74 2.40 11(DMSO-d₆, 100° C.) δ 8.17 (d, J = 9.9 Hz, 1H), 8.15 (s, 1H), 7.40-7.20(m, 15H), mono-Formate 7.10 (d, J = 8.3 Hz, 1H), 7.01-6.94 (m, 3H),6.87-6.84 (m, 1H), 6.47 (d, J = 9.9 Hz, 1H), 5.09 (dd, J = 4.6, 7.7 Hz,1H), 4.63 (s, 2H), 4.43-4.34 (m, 1H), 4.05 (d, J = 6.3 Hz, 2H), 3.81 (s,2H), 3.76-3.49 (m, 4H), 3.45-3.39 (m, 3H), 2.88-2.68 (m, 5H), 2.57-2.51(m, 1H), 2.06-1.99 (m, 1H), 1.97-1.90 (m, 2H), 1.78-1.77 (m, 1H),1.62-1.49 (m, 3H), 1.28-1.13 (m, 2H). 75 2.43 11 (DMSO-d₆, 100° C.) δ8.21 (s, 1H), 8.17 (d, J = 9.9 Hz, 1H), 7.86 (d, J = 6.3 Hz, 1H),mono-Formate 7.77 (d, J = 8.3 Hz, 2H), 7.41-720 (m, 13H), 7.09 (d, J =8.2 Hz, 1H), 7.00-6.94 (m, 3H), 6.91-6.87 (m, 1H), 6.47 (d, J = 9.9 Hz,1H), 5.08 (dd, J = 4.7, 7.6 Hz, 1H), 4.73 (s, 2H), 4.05 (d, J = 6.4 Hz,3H), 3.87-3.78 (m, 4H), 3.44 (s, 2H), 2.87-2.67 (m, 6H), 2.57-2.46 (m,1H), 2.11-1.89 (m, 3H), 1.82-1.56 (m, 3H), 1.56-1.49 (m, 2H), 1.24-1.13(m, 2H). 76 2.40 11 (DMSO-d₆, 100° C.) δ 8.19-8.14 (m, 3H), 7.82 (d, J =8.3 Hz, 2H), 7.46-7.38 (m, mono-Formate 4H), 7.35-7.23 (m, 9H), 7.10 (d,J = 8.2 Hz, 1H), 7.00-6.95 (m, 3H), 6.90 (dd, J = 2.0, 8.2 Hz, 1H), 6.49(d, J = 9.9 Hz, 1H), 6.07 (s, 1H), 5.16 (dd, J = 4.6, 7.8 Hz, 1H), 4.64(s, 2H), 4.54-4.44 (m, 1H), 4.06 (d, J = 6.3 Hz, 2H), 3.93 (s, 2H),3.74-3.60 (m, 2H), 3.51 (s, 2H), 3.46-3.39 (m, 1H), 2.90-2.77 (m, 4H),2.57-2.47 (m, 1H), 2.25-2.12 (m, 1H), 2.04-1.97 (m, 3H), 1.65-1.51 (m,3H), 1.28-1.16 (m, 2H). 77 2.40 11 (DMSO-d₆, 100° C.) δ 8.19-8.15 (m,2H), 7.40-7.20 (m, 15H), 7.10 (d, J = 8.3 Hz, mono-Formate 1H),7.00-6.94 (m, 3H), 6.85 (dd, J = 1.9, 8.0 Hz, 1H), 6.47 (d, J = 9.9 Hz,1H), 5.09 (dd, J = 4.6, 7.7 Hz, 1H), 4.63 (s, 2H), 4.44-4.37 (m, 1H),4.05 (d, J = 6.3 Hz, 2H), 3.82 (s, 2H), 3.79-3.73 (m, 1H), 3.72-3.49 (m,3H), 3.45-3.42 (m, 3H), 2.95-2.71 (m, 5H), 2.57-2.50 (m, 1H), 2.08-2.01(m, 1H), 2.03-1.89 (m, 2H), 1.80-1.74 (m, 1H), 1.62-1.49 (m, 3H),1.24-1.14 (m, 2H).

The following compounds were prepared using the appropriate amine andprotected acid in the final coupling step.

N Appropriate amine protected acid Structure 78

79

80

81

82

Salt (2 eq Rt unless N (min) Method NMR data (400 MHz) stated) 78 2.3911 (MeOD); δ 8.46 (s, 2H), 8.26 (dd, J = 4.0, 9.9 Hz, 1H), 7.48 (d, J =7.8 Hz, 1H), 7.44 (s, 5H), Formate 7.41-7.37 (m, 2H), 7.36-7.24 (m, 7H),7.09-7.02 (m, 3H), 6.99-6.95 (m, 1H), 6.64 (d, J = 9.6 Hz, 1H),5.44-5.38 (m, 1H), 4.77-4.68 (m, 1H), 4.62 (t, J = 8.6 Hz, 1H), 4.52 (s,2H), 4.50-4.42 (m, 1H), 4.33-4.26 (m, 3H), 4.18-4.10 (m, 3H), 4.07 (s,2H), 3.95 (s, 3H), 3.27 (d, J = 12.4 Hz, 2H), 3.19 (d, J = 8.6 Hz, 2H),2.72 (ddd, J = 12.6, 12.6, 2.5 Hz, 2H), 1.94-1.82 (m, 1H), 1.74 (d, J =12.9 Hz, 2H), 1.47-1.36 (m, 2H). 79 2.47 11 (MeOD); δ 8.55 (s, 1H), 8.28(d, J = 9.9 Hz, 1H), 7.45-7.23 (m, 13H), 7.08 (d, J = 1.3 Hz, 1H), mono-7.06-6.99 (m, 4H), 6.93 (dq, J = 0.7, 3.6 Hz, 1H), 6.65 (d, J = 9.9 Hz,1H), 5.34 (dd, J = 5.2, 8.0 Hz, formate 1H), 4.77 (s, 2H), 4.18 (s, 2H),4.10 (d, J = 6.3 Hz, 2H), 3.91 (s, 3H), 3.77 (s, 4H), 3.61-3.50 (m, 4H),3.42 (s, 2H), 3.10-3.02 (m, 4H), 2.33 (dd, J = 10.2, 11.7 Hz, 2H),1.80-1.69 (m, 1H), 1.63 (d, J = 15.7 Hz, 6H), 1.57-1.47 (m, 4H),1.38-1.24 (m, 2H). 80 2.44 11 (DMSO-d₆); δ 10.32 (s, 2H), 9.23-9.19 (m,1H), 8.72-8.67 (m, 2H), 8.45 (dd, J = 5.7, 5.7 Hz, TFA 1H), 7.89 (d, J =11.9 Hz, 1H), 7.35 (d, J = 2.8 Hz, 3H), 7.30 (s, 6H), 7.16 (d, J = 4.3Hz, 7H), 6.97 (d, J = 8.3 Hz, 1H), 6.81 (d, J = 8.1 Hz, 1H), 6.75-6.69(m, 2H), 6.65 (dd, J = 2.4, 8.2 Hz, 1H), 6.40 (d, J = 9.9 Hz, 1H), 5.18(dd, J = 4.5, 7.6 Hz, 1H), 4.59 (d, J = 3.3 Hz, 2H), 4.12-4.03 (m, 6H),3.87-3.79 (m, 4H), 3.67-3.63 (m, 1H), 3.16 (d, J = 11.4 Hz, 2H),3.06-2.98 (m, 2H), 2.92-2.68 (m, 5H), 1.67-1.64 (m, 2H), 1.61-1.48 (m,5H), 1.24-1.13 (m, 2H), 1.03-0.97 (m, 1H), 0.84 (dd, J = 6.8, 12.1 Hz,1H). 81 2.49 11 (MeOD); δ 8.54 (s, 1H), 8.32 (d, J = 9.9 Hz, 1H),7.45-7.26 (m, 13H), 7.23 (d, J = 4.5 Hz, 1H), mono- 7.16-7.10 (m, 1H),7.07-7.02 (m, 2H), 7.00 (s, 1H), 6.94 (dd, J = 2.3, 8.2 Hz, 1H), 6.66(d, formate J = 9.8 Hz, 1H), 5.38 (dd, J = 4.6, 8.4 Hz, 1H), 4.78 (s,2H), 4.19 (s, 2H), 4.12 (dd, J = 2.6, 6.2 Hz, 2H), 3.96 (s, 2H), 3.90(s, 3H), 3.81-3.74 (m, 2H), 3.58-3.52 (m, 4H), 3.28-3.08 (m, 6H), 2.57(dd, J = 11.4, 11.4 Hz, 2H), 1.87-1.79 (m, 1H), 1.70-1.31 (m, 12H). 822.41 11 (MeOD); δ 8.50 (s, 2H), 8.33 (d, J = 9.8 Hz, 1H), 7.44 (s, 5H),7.41-7.25 (m, 9H), 7.14 (d, formate J = 7.4 Hz, 1H), 7.10-7.02 (m, 3H),6.97 (dd, J = 2.4, 8.2 Hz, 1H), 6.67 (d, J = 9.7 Hz, 1H), 5.41 (dd, J =6.2, 6.2 Hz, 1H), 4.73-4.65 (m, 1H), 4.53 (s, 2H), 4.46-4.39 (m, 1H),4.24 (s, 2H), 4.23-4.18 (m, 1H), 4.13 (d, J = 6.2 Hz, 2H), 4.11-4.07 (m,1H), 4.05 (s, 2H), 4.00-3.95 (m, 1H), 3.93 (s, 3H), 3.26 (d, J = 12.2Hz, 2H), 3.16 (d, J = 6.3 Hz, 2H), 2.69 (dd, J = 11.6, 11.6 Hz, 2H),1.89-1.85 (m, 1H), 1.75 (d, J = 12.8 Hz, 2H), 1.48-1.30 (m, 2H).

The following compounds were prepared as described in Example 20 with(R)-4-(2-((tert-butoxycarbonyl)(2-((tert-butyldimethylsilyl)oxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzoicacid (prepared in Procedure 5) replacing(R)-4-(((tert-butoxycarbonyl)(2-((tert-butyldimethylsilyl)oxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzoicacid and the use of the appropriate amine replacingN-(tert-butoxycarbonyl)ethylenediamine HCl in Step 1.

N Appropriate amine Structure 83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

Salt N Rt (min) Method NMR data (400 MHz) (2 eq unless stated) 83 2.4511 (MeOD); δ 8.38 (d, J = 9.9 Hz, 1H), 7.82 (d, J = 8.3 Hz, 1H), 7.75(d, J = 8.3 Hz, 1H), TFA 7.48 (s, 5H), 7.43-7.29 (m, 9H), 7.23-7.15 (m,1H), 7.04 (dd, J = 8.3, 8.3 Hz, 2H), 6.93 (dd, J = 2.2, 2.2 Hz, 1H),6.89-6.81 (m, 1H), 6.70 (d, J = 9.9 Hz, 1H), 5.42 (dd, J = 6.7, 6.7 Hz,1H), 4.80 (ddd, J = 12.7, 12.7, 12.7 Hz, 2H), 4.28 (t, J = 9.7 Hz, 2H),4.13-4.06 (m, 2H), 3.59-3.43 (m, 7H), 3.37-3.35 (m, 2H), 3.29 (d, J =5.8 Hz, 2H), 3.16-3.08 (m, 3H), 3.01-2.92 (m, 2H), 1.96-1.95 (m, 1H),1.81-1.76 (m, 2H), 1.42-1.30 (m, 2H), 1.25-1.12 (m, 3H). 84 2.40 11(MeOD); δ 8.37 (d, J = 9.9 Hz, 1H), 7.81 (d, J = 8.3 Hz, 1H), 7.74 (d, J= 8.2 Hz, 1H), TFA 7.51-7.46 (m, 6H), 7.41-7.29 (m, 8H), 7.15 (q, J =7.9 Hz, 1H), 7.05 (d, J = 8.3 Hz, 1H), 7.00 (d, J = 8.2 Hz, 1H),6.93-6.91 (m, 1H), 6.82 (ddd, J = 5.7, 10.6, 17.0 Hz, 1H), 6.70 (d, J =9.8 Hz, 1H), 5.45-5.40 (m, 1H), 4.84-4.76 (m, 2H), 4.26 (d, J = 8.0 Hz,2H), 4.11-4.05 (m, 2H), 3.61-3.35 (m, 7H), 3.29 (d, J = 7.5 Hz, 2H),3.12 (s, 3H), 3.08 (d, J = 7.8 Hz, 1H), 3.00 (s, 1H), 2.99-2.92 (m, 2H),1.95-1.89 (m, 1H), 1.80-1.69 (m, 3H), 1.43-1.30 (m, 2H). 85 2.43 11(MeOD); δ 8.37 (d, J = 9.9 Hz, 1H), 7.84 (d, J = 8.4 Hz, 2H), 7.52-7.48(m, 6H), TFA 7.40 (dd, J = 8.6, 8.6 Hz, 4H), 7.35-7.28 (m, 6H),7.07-7.04 (m, 3H), 6.98 (dd, J = 2.1, 8.8 Hz, 1H), 6.70 (d, J = 9.8 Hz,1H), 5.45-5.40 (m, 1H), 4.51 (s, 2H), 4.27 (s, 2H), 4.11 (d, J = 6.3 Hz,2H), 3.49-3.35 (m, 6H), 3.32-3.28 (m, 3H), 3.19-3.10 (m, 3H), 2.97 (dd,J = 10.9, 12.7 Hz, 2H), 2.01-1.93 (m, 1H), 1.84-1.77 (m, 4H), 1.47-1.37(m, 2H). 86 2.43 11 (MeOD); δ 8.38 (1H, d, J = 9.9 Hz), 7.53-7.49 (6H,m), 7.46 (4H, d, J = 4.3 Hz), TFA 7.41-7.26 (6H, m), 7.06 (2H, d, J =8.2 Hz), 6.97 (1H, s), 6.94 (1H, d, J = 7.2 Hz), 6.71 (1H, d, J = 9.9Hz), 5.43 (1H, dd, J = 5.6, 7.8 Hz), 4.84 (2H, s), 4.28 (2H, s),4.17-4.08 (1H, m), 3.69 (6H, m), 3.51-3.37 (4H, m), 3.30 (2H, s),3.20-3.11 (3H, m), 3.01-2.93 (2H, m), 1.98-1.92 (1H, m), 1.84-1.77 (4H,m), 1.47-1.33 (2H, m) 87 2.57 11 (MeOD); δ 8.37 (dd, J = 2.1, 9.9 Hz,1H), 7.81 (d, J = 8.4 Hz, 1H), 7.75 (d, J = 8.2 Hz, TFA 1H), 7.42-7.23(m, 16H), 7.22-7.14 (m, 1H), 7.07-6.95 (m, 4H), 6.87 (dd, J = 1.9, 7.3Hz, 1H), 6.79 (dd, J = 2.3, 8.1 Hz, 1H), 6.70 (d, J = 9.8 Hz, 1H), 5.42(dd, J = 6.3, 6.3 Hz, 1H), 5.02-4.97 (m, 1H), 4.81 (t, J = 4.4 Hz, 1H),4.70 (d, J = 5.9 Hz, 2H), 4.26 (s, 2H), 4.19 (s, 2H), 3.63-3.49 (m, 5H),3.16-3.10 (m, 2H), 2.93-2.93 (m, 3H), 1.79 (dt, J = 15.4, 39.6 Hz, 5H),1.31 (s, 3H). 88 2.45 11 (MeOD); δ 8.37 (d, J = 9.9 Hz, 1H), 7.86 (d, J= 8.4 Hz, 2H), 7.53-7.48 (m, 5H), TFA 7.43 (d, J = 8.4 Hz, 2H),7.41-7.29 (m, 7H), 7.10-7.04 (m, 3H), 6.98 (dd, J = 2.0, 8.2 Hz, 1H),6.71 (d, J = 9.8 Hz, 1H), 5.42 (dd, J = 5.3, 8.2 Hz, 1H), 4.60-4.43 (m,5H), 4.28 (s, 2H), 4.13 (d, J = 6.4 Hz, 2H), 3.50-3.41 (m, 4H),3.20-3.11 (m, 3H), 3.01-2.95 (m, 2H), 2.54-2.42 (m, 4H), 2.05-1.75 (m,3H), 1.50-1.32 (m, 2H). 89 2.46 11 (MeOD); δ 8.54 (d, J = 1.9 Hz, 1H),8.37 (d, J = 9.9 Hz, 1H), 7.84 (d, J = 8.3 Hz, 2H), TFA 7.53-7.48 (m,5H), 7.43 (d, J = 8.3 Hz, 2H), 7.41-7.29 (m, 6H), 7.29-7.24 (m, 1H),7.05 (d, J = 8.2 Hz, 2H), 6.95-6.89 (m, 2H), 6.70 (d, J = 9.9 Hz, 1H),5.42 (dd, J = 5.8, 7.8 Hz, 1H), 4.83-4.72 (m, 2H), 4.42 (s, 1H), 4.27(s, 2H), 4.18-4.10 (m, 2H), 3.94 (d, J = 12.8 Hz, 1H), 3.49-3.35 (m,7H), 3.20-3.07 (m, 4H), 2.97 (dd, J = 12.5, 12.5 Hz, 2H), 2.67 (s, 1H),1.95 (d, J = 3.0 Hz, 2H), 1.78 (dd, J = 13.9, 15.6 Hz, 4H), 1.45-1.31(m, 2H), 1.25-1.11 (m, 2H). 90 2.51 11 (MeOD); δ 8.37 (d, J = 9.9 Hz,1H), 7.83 (d, J = 8.3 Hz, 2H), 7.53-7.48 (m, 6H), TFA 7.44-7.28 (m, 8H),7.09-7.04 (m, 3H), 6.96 (dd, J = 2.3, 8.3 Hz, 1H), 6.71 (d, J = 9.9 Hz,1H), 5.42 (dd, J = 5.3, 8.2 Hz, 1H), 4.48 (s, 2H), 4.29 (s, 2H), 4.13(d, J = 6.3 Hz, 2H), 3.90-3.72 (m, 2H), 3.38 (d, J = 6.3 Hz, 5H), 3.30(s, 1H), 3.16-3.10 (m, 3H), 3.01-2.94 (m, 2H), 2.01 (s, 2H), 1.95-1.81(m, 5H), 1.52-1.41 (m, 5H). 91 2.46 11 (MeOD); δ 8.38 (d, J = 9.9 Hz,1H), 7.53-7.48 (m, 6H), 7.43 (s, 4H), 7.40-7.27 (m, TFA 6H), 7.09-7.03(m, 3H), 6.96 (dd, J = 2.3, 8.1 Hz, 1H), 6.71 (d, J = 9.8 Hz, 1H), 5.42(dd, J = 5.3, 8.1 Hz, 1H), 4.58-4.44 (m, 2H), 4.35-4.27 (m, 3H), 4.28(s, 2H), 4.12 (d, J = 6.3 Hz, 2H), 4.05-3.98 (m, 1H), 3.73-3.68 (m, 1H),3.51-3.40 (m, 2H), 3.24-3.09 (m, 3H), 3.06-2.93 (m, 3H), 2.06-1.67 (m,6H), 1.61-1.36 (m, 5H); 92 2.44 11 (MeOD); δ 8.37 (d, J = 9.9 Hz, 1H),7.85 (d, J = 6.8 Hz, 2H), 7.53-7.49 (m, 4H), TFA 7.45-7.25 (m 11H),7.08-6.91 (m, 3H), 6.70 (d, J = 9.8 Hz, 1H), 5.42 (dd, J = 5.6, 8.0 Hz,1H), 4.85-4.77 (m, 2H), 4.52-4.43 (m, 1H), 4.28 (s, 2H), 4.19-4.08 (m,2H), 4.01-3.97 (m, 1H), 3.50-3.35 (m, 6H), 3.30-3.08 (m, 4H), 3.04-2.83(m, 3H), 2.08-1.95 (m, 3H), 1.79 (s, 1H), 1.65-1.50 (m, 2H), 1.42-1.31(m, 2H). 93 2.53 11 (MeOD); δ 8.38 (d, J = 9.9 Hz, 1H), 7.66 (d, J = 8.3Hz, 2H), 7.51-7.50 (m, 5H), TFA 7.43 (d, J = 8.2 Hz, 2H), 7.41-7.35 (m,6H), 7.33-7.26 (m, 1H), 7.09-7.03 (m, 2H), 6.97-6.89 (m, 2H), 6.70 (d, J= 9.9 Hz, 1H), 5.43 (dd, J = 5.8, 7.6 Hz, 1H), 4.54-4.41 (m, 4H), 4.30(d, J = 14.1 Hz, 4H), 4.19-4.10 (m, 4H), 3.47-3.35 (m, 4H), 3.29 (d, J =7.3 Hz, 2H), 3.20-3.10 (m, 3H), 3.01-2.88 (m, 2H), 1.95 (d, J = 3.8 Hz,1H), 1.80-1.78 (m, 2H), 1.49-1.29 (m, 3H) 94 2.54 11 (MeOD); δ 8.37 (d,J = 9.9 Hz, 1H), 7.69 (d, J = 8.3 Hz, 2H), 7.53-7.48 (m, 5H), TFA 7.44(d, J = 8.2 Hz, 4H), 7.40-7.25 (m, 5H), 7.05 (d, J = 8.2 Hz, 2H),6.94-6.90 (m, 2H), 6.71 (d, J = 9.8 Hz, 1H), 5.42 (dd, J = 5.1, 8.3 Hz,1H), 4.79 (dd, J = 4.1, 4.1 Hz, 2H), 4.28 (s, 2H), 4.14-4.10 (m, 4H),3.95 (s, 2H), 3.59-337 (m, 6H), 3.17-3.10 (m, 3H), 3.02-2.94 (m, 2H),1.96 (s, 1H), 1.85-1.74 (m, 9H), 1.46-1.35 (m, 2H). 95 2.60 11 (MeOD); δ8.38 (d, J = 9.9 Hz, 1H), 7.53-7.47 (m, 6H), 7.43 (s, 4H), 7.41-7.25 (m,TFA 6H), 7.05 (d, J = 8.2 Hz, 2H), 6.97-6.90 (m, 2H), 6.71 (d, J = 9.8Hz, 1H), 5.42 (dd, J = 5.1, 8.3 Hz, 1H), 4.79-4.77 (m, 2H), 4.28 (s,2H), 4.16-4.09 (m, 2H), 3.77-3.77 (m, 2H), 3.57-3.36 (m, 10H), 3.30 (d,J = 5.3 Hz, 2H), 3.19-3.10 (m, 3H), 3.01-2.94 (m, 2H), 1.96-1.92 (m,1H), 1.79 (dd, J = 12.9, 12.9 Hz, 2H), 1.70-1.47 (m, 7H), 1.44-1.31 (m,2H). 96 2.53 11 (MeOD); δ 8.38 (dd, J = 5.6, 8.4 Hz, 1H), 7.54-7.48 (m,6H), 7.43 (s, 4H), TFA 7.40-7.27 (m, 6H), 7.06 (dd, J = 7.7, 7.7 Hz,2H), 6.96 (s, 1H), 6.92 (dd, J = 2.3, 8.0 Hz, 1H), 6.71 (d, J = 9.9 Hz,1H), 5.42 (dd, J = 5.0, 8.4 Hz, 1H), 4.62 (s, 2H), 4.28 (s, 2H), 4.13(d, J = 6.1 Hz, 2H), 4.09-4.01 (m, 2H), 3.75 (s, 3H), 3.51-3.35 (m, 5H),3.30 (d, J = 5.0 Hz, 2H), 3.16-3.10 (m, 3H), 3.02-2.94 (m, 2H),2.01-1.96 (m, 1H), 1.80-1.80 (m, 7H), 1.47-1.42 (m, 2H). 97 2.49 11(MeOD); δ 8.38 (d, J = 9.9 Hz, 1H), 7.53-7.49 (m, 5H), 7.48 (s, 1H),7.42-7.29 (m, TFA 10H), 7.05 (d, J = 8.2 Hz, 3H), 6.96 (dd, J = 2.0, 8.2Hz, 1H), 6.70 (d, J = 9.8 Hz, 1H), 5.42 (dd, J = 5.3, 8.3 Hz, 1H),4.65-4.50 (m, 3H), 4.28 (s, 2H), 4.12 (d, J = 6.3 Hz, 2H), 3.75-3.62 (m,1H), 3.51-3.38 (m, 5H), 3.18-3.08 (m, 5H), 3.02-2.94 (m, 4H), 2.01-1.94(m, 1H), 1.85-1.77 (m, 4H), 1.60 (s, 1H), 1.48-1.29 (m, 2H), 1.16-1.16(m, 2H). 98 2.47 11 (DMSO-d₆) δ 8.17 (d, J = 9.9 Hz, 1H), 7.32-7.22 (m,16H), 7.05 (d, J = 8.3 Hz, 1H), Free Base 6.94-6.87 (m, 3H), 6.84-6.84(m, 1H), 6.49 (d, J = 9.9 Hz, 1H), 5.01 (dd, J = 4.5, 7.8 Hz, 1H),4.58-4.47 (m, 2H), 4.03-3.97 (m, 2H), 3.85-3.83 (m, 2H), 3.60-3.52 (m,2H), 3.30 (m, 3H), 2.84-2.67 (m, 8H), 1.87-1.72 (m, 5H), 1.53-1.40 (m,6H), 1.16-1.05 (m, 3H) 99 2.50 11 (MeOD); δ 8.52 (s, 2H), 8.37 (d, J =9.9 Hz, 1H), 7.39 (s, 9H), 7.37-7.22 (m, 6H), Formate 7.04-6.93 (m, 5H),6.69 (d, J = 9.9 Hz, 1H), 5.38 (dd, J = 4.3, 9.0 Hz, 1H), 4.89-4.74 (m,2H), 4.05 (d, J = 5.9 Hz, 2H), 3.86-3.83 (m, 2H), 161-3.04 (m, 19H),2.39 (s, 1H), 1.60-1.56 (m, 6H), 1.43-1.42 (m, 1H), 1.35-1.29 (m, 4H).100 2.44 11 (DMSO-d₆, 100° C.) δ 8.18 (1H, d, J = 9.9 Hz), 7.47 (5H, s),7.39-7.22 (10H, m), TFA 7.16 (1H, d, J = 8.2 Hz), 7.04-6.97 (3H, m),6.89 (1H, dd, J = 2.1, 7.8 Hz), 6.58 (1H, d, J = 9.8 Hz), 5.36 (1H, dd,J = 4.9, 8.3 Hz), 4.74 (2H, s), 4.21 (3H, m), 4.06 (3H, m), 3.67 (5H,dd, J = 5.0, 5.0 Hz), 3.48 (2H, dd, J = 4.8, 4.8 Hz), 3.41-3.19 (8H, m),3.10-3.04 (2H, m), 2.98-2.77 (2H, m), 2.56-2.54 (1H, m), 1.89 (1H, s),1.78-1.74 (3H, m), 1.57-1.40 (3H, m); 101 2.42 11 (MeOD); δ 8.47 (s,2H), 8.37 (d, J = 9.9 Hz, 1H), 7.87 (d, J = 7.9 Hz, 2H), 7.45-7.28 (m,Formate 14H), 7.07-7.03 (m, 2H), 7.01-6.91 (m, 2H), 6.70 (d, J = 9.8 Hz,1H), 5.41 (dd, J = 5.5, 8.0 Hz, 1H), 4.84-4.76 (m, 1H), 4.69-4.63 (m,1H), 4.62 (d, J = 2.1 Hz, 2H), 4.41-4.27 (m, 2H), 4.14-4.07 (m, 6H),3.29-3.23 (m, 4H), 3.16-3.08 (m, 3H), 2.78-2.67 (m, 2H), 1.94-1.85 (m,1H), 1.76-1.72 (m, 2H), 1.45-1.34 (m, 2H) 102 2.43 11 (MeOD); δ 8.47 (s,2H), 8.37 (d, J = 9.9 Hz, 1H), 7.87 (d, J = 7.9 Hz, 2H), 7.45-7.28 (m,Formate 14H), 7.07-7.03 (m, 2H), 7.01-6.91 (m, 2H), 6.70 (d, J = 9.8 Hz,1H), 5.41 (dd, J = 5.5, 8.0 Hz, 1H), 4.84-4.76 (m, 1H), 4.69-4.63 (m,1H), 4.62 (d, J = 2.1 Hz, 2H), 4.41-4.27 (m, 2H), 4.14-4.07 (m, 6H),3.29-3.23 (m, 4H), 3.16-3.08 (m, 3H), 2.78-2.67 (m, 2H), 1.94-1.85 (m,1H), 1.76-1.72 (m, 2H), 1.45-1.34 (m, 2H) 103 2.41 11 (MeOD); δ 8.41 (d,J = 9.9 Hz, 1H), 7.78 (d, J = 8.3 Hz, 2H), 7.50 (s, 5H), 7.42-7.24 (m,TFA 9H), 7.06 (d, J = 8.3 Hz, 3H), 6.97-6.93 (m, 1H), 6.72 (d, J = 9.8Hz, 1H), 5.45 (dd, J = 6.8, 6.8 Hz, 1H), 4.50 (s, 2H), 4.28 (s, 2H),4.10 (d, J = 6.4 Hz, 2H), 3.54-3.37 (m, 9H), 3.21-3.10 (m, 3H),3.02-2.93 (m, 2H), 2.01-1.93 (m, 1H), 1.84-1.74 (m, 2H), 1.49-1.37 (m,2H). 104 2.39 11 (DMSO, 100° C.); δ 8.21 (d, J = 9.9 Hz, 1H), 8.17 (s,1H), 7.92-7.92 (m, 1H), mono Formate 7.39-7.24 (m, 15H), 7.08 (d, J =8.2 Hz, 1H), 7.04-7.00 (m, 2H), 6.95 (d, J = 8.2 Hz, 1H), 6.90 (dd, J =2.4, 8.0 Hz, 1H), 6.49 (d, J = 9.9 Hz, 1H), 5.04 (dd, J = 5.0, 7.5 Hz,1H), 4.43 (s, 2H), 4.37 (br s, 1H), 4.05 (d, J = 6.3 Hz, 2H), 3.71 (dd,J = 6.7, 11.4 Hz, 1H), 3.60-3.49 (m, 2H), 3.44 (s, 2H), 3.36 (dd, J =5.3, 11.4 Hz, 2H), 2.91-2.72 (m, 6H), 2.17-2.07 (m, 1H), 1.97-1.86 (m,3H), 1.62-1.48 (m, 3H), 1.28-1.13 (m, 2H). 105 2.44 11 (DMSO-d₆, 100°C.); δ 8.21 (d, J = 9.9 Hz, 1H), 8.16 (s, 2H), 7.57 (d, J = 8.4 Hz, 1H),Formate 7.40-7.21 (m, 15H), 7.10-7.04 (m, 2H), 7.01 (d, J = 8.0 Hz, 1H),6.95 (d, J = 8.2 Hz, 1H), 6.91 (dd, J = 2.3, 8.2 Hz, 1H), 6.49 (d, J =9.9 Hz, 1H), 5.06-5.02 (m, 1H), 4.41 (s, 2H), 4.04 (d, J = 6.3 Hz, 2H),3.93-3.69 (m, 4H), 3.43 (s, 2H), 3.13-3.04 (m, 4H), 2.91-2.68 (m, 7H),1.98-1.90 (m, 2H), 1.69-1.48 (m, 4H), 1.24-1.13 (m, 2H). 106 2.47 11(DMSO-d₆, 100° C.); δ 8.21 (d, J = 9.9 Hz, 1H), 8.17 (s, 1H), 7.57 (d, J= 7.4 Hz, 1H), mono Formate 7.41-7.37 (m, 2H), 7.32-7.22 (m, 12H),7.10-7.00 (m, 3H), 6.95 (d, J = 8.0 Hz, 1H), 6.90 (dd, J = 2.3, 8.2 Hz,1H), 6.50 (d, J = 9.9 Hz, 1H), 5.04 (dd, J = 4.9, 7.4 Hz, 1H), 4.41 (d,J = 2.5 Hz, 2H), 4.05 (d, J = 6.3 Hz, 2H), 3.92 (d, J = 12.5 Hz, 1H),3.85-3.77 (m, 1H), 3.72 (d, J = 11.8 Hz, 1H), 3.44 (s, 2H), 3.13-3.02(m, 2H), 2.91-2.72 (m, 8H), 2.57-2.47 (m, 1H), 1.97-1.85 (m, 3H),1.72-1.48 (m, 6H), 1.28-1.13 (m, 2H). 107 240 11 (DMSO-d₆, 100° C.); δ8.20 (d, J = 9.9 Hz, 1H), 7.97 (d, J = 6.1 Hz, 1H), 7.51-7.47 (m, TFA6H), 7.41-7.24 (m, 9H), 7.17 (d, J = 8.3 Hz, 1H), 7.04-7.00 (m, 3H),6.90 (dd, J = 2.1, 8.2 Hz, 1H), 6.58 (d, J = 9.8 Hz, 1H), 5.38 (dd, J =4.8, 8.3 Hz, 1H), 4.43 (s, 2H), 4.33 (dd, J = 6.3, 12.4 Hz, 1H), 4.23(s, 2H), 4.10 (d, J = 5.3 Hz, 2H), 3.72 (dd, J = 6.8, 11.4 Hz, 1H),3.61-3.48 (m, 4H), 3.14-3.05 (m, 6H), 2.99-2.95 (m, 2H), 2.57-2.55 (m,1H), 2.17-2.05 (m, 1H), 1.94-1.85 (m, 2H), 1.79-1.75 (m, 2H), 1.45-1.44(m, 2H). 108 2.44 11 (DMSO-d₆, 100° C.); δ 8.21-8.19 (m, 2H), 7.85-7.80(m, 1H), 7.75 (d, J = 8.2 Hz, mono-formate 2H), 7.41-7.38 (m, 2H),7.33-7.22 (m, 11H), 7.08 (d, J = 8.2 Hz, 1H), 7.00-6.94 (m, 3H),6.90-6.87 (m, 1H), 6.49 (d, J = 9.9 Hz, 1H), 5.03 (dd, J = 5.0, 7.5 Hz,1H), 4.73 (s, 2H), 4.06-4.03 (m, 3H), 3.88-3.87 (m, 2H), 3.74-3.68 (m,1H), 3.44 (s, 2H), 3.13-2.97 (m, 1H), 2.93-2.71 (m, 8H), 2.57-2.47 (m,1H), 2.05-1.89 (m, 3H), 1.82-1.76 (m, 1H), 1.72-1.46 (m, 4H), 1.24-1.13(m, 2H). 109 2.41 11 (DMSO, 100° C.); δ 8.21-8.17 (m, 3H), 8.12 (s, 1H),7.76 (d, J = 8.2 Hz, 2H), 7.39 (dd, formate J = 1.4, 8.3 Hz, 2H),7.35-7.22 (m, 11H), 7.08 (d, J = 8.2 Hz, 1H), 7.00-6.94 (m, 3H), 6.89(dd, J = 1.9, 8.2 Hz, 1H), 6.49 (d, J = 9.9 Hz, 1H), 5.03 (dd, J = 5.0,7.5 Hz, 1H), 4.64 (s, 2H), 4.53 (s, 1H), 4.05 (d, J = 6.3 Hz, 2H),3.88-3.58 (m, 2H), 3.43 (s, 2H), 2.91-2.71 (m, 9H), 2.56-2.45 (m, 1H),2.17 (br s, 1H), 2.05 (br s, 1H), 1.98-1.90 (m, 2H), 1.63-1.49 (m, 3H),1.28-1.13 (m, 2H). 110 2.43 11 (DMSO-d₆, 100° C.); δ 8.20 (d, J = 9.9Hz, 1H), 8.16-8.11 (m, 2H), 7.77 (d, J = 8.3 Hz, mono-formate 2H), 7.39(dd, J = 1.4, 8.3 Hz, 2H), 7.35-7.21 (m, 11H), 7.09 (d, J = 8.3 Hz, 1H),7.00-6.95 (m, 3H), 6.89 (dd, J = 2.0, 8.2 Hz, 1H), 6.50 (d, J = 9.9 Hz,1H), 6.10 (s, 1H), 5.09 (dd, J = 4.9, 7.5 Hz, 1H), 4.64 (s, 2H),4.54-4.45 (m, 1H), 4.05 (d, J = 6.3 Hz, 2H), 3.72-3.59 (m, 2H),3.47-3.40 (m, 3H), 3.00-2.73 (m, 8H), 2.57-2.47 (m, 1H), 2.17 (br s,1H), 2.04-1.91 (m, 3H), 1.63-1.55 (m, 1H), 1.52 (d, J = 13.2 Hz, 2H),1.25-1.14 (m, 2H). 111 2.41 11 (DMSO-d₆); δ 8.21 (d, J = 9.8 Hz, 1H),8.16 (s, 2H), 7.40-7.20 (m, 15H), 7.08 (d, formate J = 8.4 Hz, 1H),7.00-6.94 (m, 3H), 6.85 (dd, J = 1.9, 8.0 Hz, 1H), 6.50 (d, J = 9.0 Hz,1H), 5.04 (dd, J = 5.0, 7.4 Hz, 1H), 4.63 (s, 2H), 4.43-4.37 (m, 1H),4.04 (d, J = 6.4 Hz, 2H), 3.79-3.73 (m, 1H), 3.72-3.49 (m, 4H),3.46-3.39 (m, 3H), 2.95-2.73 (m, 8H), 2.57-2.47 (m, 1H), 2.06-2.00 (m,1H), 1.97-1.89 (m, 2H), 1.81-1.76 (m, 1H), 1.62-1.49 (m, 3H), 1.28-1.13(m, 2H). 112 2.42 11 (DMSO-d₆, 100° C.); δ 8.21 (d, J = 9.9 Hz, 1H),8.16 (s, 1H), 7.41-7.20 (m, 15H), mono-formate 7.08 (d, J = 8.4 Hz, 1H),7.00-6.94 (m, 3H), 6.87-6.84 (m, 1H), 6.50 (d, J = 9.9 Hz, 1H), 5.04(dd, J = 5.0, 7.4 Hz, 1H), 4.63 (s, 2H), 4.44-4.36 (m, 1H), 4.05 (d, J =6.3 Hz, 2H), 3.81-3.75 (m, 1H), 3.72-3.49 (m, 4H), 3.46-3.40 (m, 3H),2.94-2.72 (m, 8H), 2.58-2.50 (m, 1H), 2.08-2.01 (m, 1H), 1.97-1.89 (m,2H), 1.80-137 (m, 1H), 1.62-1.49 (m, 3H), 1.28-1.13 (m, 2H). 113 2.45 11(DMSO-d₆, 100° C.); δ 8.22-8.18 (m, 2H), 7.84 (d, J = 5.4 Hz, 1H), 7.74(d, J = 8.2 Hz, mono-formate 2H), 7.39 (dd, J = 1.3, 8.3 Hz, 2H),7.33-7.22 (m, 11H), 7.08 (d, J = 8.2 Hz, 1H), 7.01-6.94 (m, 3H),6.91-6.87 (m, 1H), 6.49 (d, J = 9.9 Hz, 1H), 5.03 (dd, J = 5.0, 7.5 Hz,1H), 4.73 (s, 2H), 4.05 (d, J = 6.4 Hz, 3H), 3.91-3.84 (m, 2H), 3.43 (s,2H), 3.10-3.00 (m, 2H), 2.91-2.68 (m, 7H), 2.57-2.46 (m, 1H), 2.00-1.89(m, 3H), 1.83-1.49 (m, 6H), 1.24-1.13 (m, 2H).

Example 21, (1-Benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-((4-(((1R,3S)-3-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)-ethyl)benzamido)cyclobutyl)carbamoyl)benzyl)oxy)phenyl)-2-phenylacetate(Compound 114)

Step 1; (1-Benzylpiperidin-4-yl)methyl(S)-2-(3-((4-(((1r,3S)-3-((tert-butoxycarbonyl)amino)cyclobutyl)carbamoyl)benzyl)oxy)phenyl)-2-hydroxy-2-phenylacetate

To a stirred solution of(S)-4-((3-(2-((1-benzylpiperidin-4-yl)methoxy)-1-hydroxy-2-oxo-1-phenylethyl)phenoxy)methyl)benzoicacid hydrochloride (0.20 g, 0.33 mmol) in DMF (1.9 mL) was added DIPEA(0.132 mL, 0.76 mmol) and HATU (0.173 g, 0.46 mmol) and the mixturestirred at room temperature for 30 minutes. To this mixture was added asolution of tert-butyl trans-(3-aminocyclobutyl)carbamate hydrochloride(0.068 g, 0.38 mmol) and DIPEA (0.13 mL, 0.76 mmol) in DMF (1.9 mL). Thereaction mixture diluted with ethyl acetate and washed with 2M aqueoussodium hydroxide and brine. The organic phase was dried over magnesiumsulfate, filtered and the filtrate evaporated at reduced pressure toafford the title compound (0.247 g, >100%).

¹H NMR (400 MHz, DMSO-d₆); δ 8.67 (d, J=6.9 Hz, 1H), 7.86 (d, J=8.3 Hz,2H), 7.47 (d, J=8.3 Hz, 2H), 7.33-7.24 (m, 12H), 6.96 (d, J=5.9 Hz, 2H),6.92 (dd, J=8.1, 8.1 Hz, 1H), 6.60 (s, 1H), 5.12 (s, 2H), 4.41-4.39 (m,1H), 4.15-4.06 (m, 1H), 4.01-3.97 (m, 2H), 3.39 (s, 2H), 2.34-2.22 (m,5H), 1.82 (dd, J=11.0, 11.0 Hz, 2H), 1.46 (d, J=12.9 Hz, 3H), 1.39 (s,9H), 1.37 (s, 1H), 1.17-1.05 (m, 2H).

Step 2; (1-Benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-((4-(((1R,3S)-3-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzamido)-cyclobutyl)carbamoyl)benzyl)oxy)phenyl)-2-phenylacetate(Compound 114)

To a stirred solution of (1-benzylpiperidin-4-yl)methyl(S)-2-(3-((4-(((1r,3S)-3-((tert-butoxycarbonyl)amino)cyclobutyl)carbamoyl)benzyl)oxy)phenyl)-2-hydroxy-2-phenylacetate(0.247 g, 0.34 mmol) was added a solution of HCl in dioxan (4M, 15 mL)and the mixture stirred at room temperature for 1 hour. The solventevaporated under reduced pressure. The residue was dissolved in DMF (3ml) and added to a pre-stirred (15 minutes) mixture of(R)-4-(2-((tert-butoxycarbonyl)(2-((tert-butyldimethylsilyl)oxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzoicacid (0.196 g, 0.35 mmol), DIPEA (0.214 mL, 1.23 mmol) and HATU (0.16 g,0.42 mmol) in DMF (2 mL). The reaction mixture was stirred at roomtemperature for 18 hours. The reaction mixture dissolved in ethylacetate and washed with saturated aqueous sodium carbonate and brine.The organic phase was dried with magnesium sulfate, filtered and thefiltrate evaporated at reduced pressure. The residue was dissolved indioxan (1 mL) and a solution of HCl-dioxan (2 mL) added. The reactionmixture was stirred at room temperature for 1 hour. The solvent wasevaporated at reduced pressure and the residue purified by reversepreparative HPLC.

¹H NMR (400 MHz, DMSO-d₆); δ 8.81 (d, J=7.1 Hz, 1H), 8.74 (d, J=7.1 Hz,1H), 8.28 (s, 1H), 8.22 (d, J=9.5 Hz, 1H), 7.94 (d, J=8.3 Hz, 2H), 7.87(d, J=8.3 Hz, 2H), 7.54 (d, J=8.3 Hz, 2H), 7.37-7.28 (m, 13H), 7.13 (d,J=8.1 Hz, 1H), 7.02-6.95 (m, 4H), 6.57 (d, J=9.9 Hz, 1H), 5.18 (s, 2H),5.14 (dd, J=5.2, 7.5 Hz, 1H), 4.66-4.57 (m, 2H), 4.04 (d, J=6.3 Hz, 2H),3.44 (s, 2H), 2.97-2.83 (m, 6H), 2.77 (d, J=11.1 Hz, 2H), 2.49 (t, J=7.1Hz, 4H), 1.88 (dd, J=9.9, 11.6 Hz, 2H), 1.57-1.47 (m, 3H), 1.21-1.12 (m,2H).

The following compounds were prepared in a similar fashion using theappropriate amine:

N Appropriate amine Structure 115

116

117

118

119

120

121

122

Salt N Rt (min) Method NMR data (400 MHz) (2 eq unless stated) 114 2.5711 (DMSO-d₆); δ 8.81 (d, J = 7.1 Hz, 1H), 8.74 (d, J = 7.1 Hz, 1H), 8.28(s, 1H), TFA 8.22 (d, J = 9.5 Hz, 1H), 7.94 (d, J = 8.3 Hz, 2H), 7.87(d, J = 8.3 Hz, 2H), 7.54 (d, J = 8.3 Hz, 2H), 7.37-7.28 (m, 13H), 7.13(d, J = 8.1 Hz, 1H), 7.02-6.95 (m, 4H), 6.57 (d, J = 9.9 Hz, 1H), 5.18(s, 2H), 5.14 (dd, J = 5.2, 7.5 Hz, 1H), 4.66-4.57 (m, 2H), 4.04 (d, J =6.3 Hz, 2H), 3.44 (s, 2H), 2.97-2.83 (m, 6H), 2.77 (d, J = 11.1 Hz, 2H),2.49 (t, J = 7.1 Hz, 4H), 1.88 (dd, J = 9.9, 11.6 Hz, 2H), 1.57-1.47 (m,3H), 1.21-1.12 (m, 2H). 115 2.58 11 (DMSO-d₆); δ 8.23 (s, 1H), 8.18 (d,J = 9.9 Hz, 1H), 7.46 (d, J = 8.2 Hz, 2H), Formate 7.37 (d, J = 8.2 Hz,2H), 7.33-7.25 (m, 15H), 7.08 (d, J = 8.3 Hz, 1H), 6.98-6.91 (m, 4H),6.52 (d, J = 9.8 Hz, 1H), 5.12 (d, J = 5.9 Hz, 1H), 5.09 (s, 2H), 4.00(d, J = 6.3 Hz, 2H), 3.60 (s, 2H), 3.39 (s, 2H), 3.29 (s, 6H), 2.97-2.87(m, 2H), 2.83-2.77 (m, 4H), 2.72 (d, J = 11.3 Hz, 2H), 1.87-1.79 (m,2H), 1.53-1.45 (m, 10H), 1.17-1.08 (m, 2H). 116 2.57 11 (DMSO-d₆, 90°C.); δ 8.18 (d, J = 9.9 Hz, 1H), 7.65-7.59 (m, 3H), 7.48 (d, TFA J = 7.2Hz, 5H), 7.39-7.24 (m, 8H), 7.16 (d, J = 8.3 Hz, 1H), 7.04-6.95 (m, 3H),6.58 (d, J = 9.9 Hz, 1H), 5.36 (dd, J = 4.5, 8.5 Hz, 1H), 5.12 (s, 2H),4.35-4.33 (m, 8H), 4.22 (s, 2H), 4.06 (s, 2H), 3.34-3.29 (m, 4H),3.21-3.17 (m, 4H), 3.10-3.04 (m, 5H), 1.97-1.71 (m, 4H), 1.42-1.42 (m,2H). 117 2.57 11 (DMSO-d₆); δ 8.23 (s, 1H), 8.18 (d, J = 9.9 Hz, 1H),7.65 (d, J = 8.3 Hz, 2H), mono-Formate 7.48 (d, J = 8.3 Hz, 2H),7.32-7.24 (m, 15H), 7.08 (d, J = 8.3 Hz, 1H), 6.98-6.90 (m, 4H), 6.61(s, 1H), 6.52 (d, J = 9.9 Hz, 1H), 5.12-5.08 (m, 3H), 4.06 (s, 2H), 3.99(d, J = 6.3 Hz, 2H), 3.81 (s, 2H), 3.48 (m, 1H), 3.39 (s, 2H), 3.28 (m,3H), 2.94-2.85 (m, 2H), 2.83-2.77 (m, 4H), 2.72 (d, J = 11.4 Hz, 2H),1.87-1.72 (m, 6H), 1.53-1.45 (m, 3H), 1.16-1.07 (m, 2H). 118 2.55 11(DMSO-d₆); δ 10.55 (s, 1H), 10.45 (s, 1H), 9.40 (s, 1H), 8.75 (s, 2H),8.16 (d, TFA J = 9.9 Hz, 1H), 7.52-7.41 (m, 11H), 7.36-7.25 (m, 8H),7.17 (d, J = 8.3 Hz, 1H), 7.01-6.95 (m, 3H), 6.92 (d, J = 7.9 Hz, 1H),6.65 (s, 1H), 6.60 (d, J = 9.9 Hz, 1H), 6.15 (s, 1H), 5.34 (d, J = 8.0Hz, 1H), 5.10 (s, 2H), 4.25 (dt, J = 6.3, 18.9 Hz, 2H), 4.00 (d, J = 6.5Hz, 2H), 3.63-3.26 (m, 10H), 3.18-2.99 (m, 5H), 2.94-2.85 (m, 2H),1.84-1.83 (m, 1H), 1.75-1.66 (m, 3H), 1.35 (q, J = 11.9 Hz, 2H). 1192.55 11 (DMSO-d₆) δ 10.55 (s, 1H), 10.45 (s, 1H), 9.40 (s, 1H), 8.75 (s,2H), 8.16 (d, TFA J = 9.9 Hz, 1H), 7.63 (d, J = 8.3 Hz, 2H), 7.48 (m,7H), 7.40-7.24 (m, 10H), 7.16 (d, J = 8.3 Hz, 1H), 7.01-6.96 (m, 3H),6.92 (d, J = 8.2 Hz, 1H), 6.65 (s, 1H), 6.60 (dd, J = 2.0, 9.8 Hz, 1H),6.15 (s, 1H), 5.33 (d, J = 8.4 Hz, 1H), 5.09 (s, 2H), 4.26 (dt, J = 5.5,18.7 Hz, 2H), 4.04-3.97 (m, 4H), 3.81 (s, 2H), 3.56-3.56 (m, 2H),3.34-3.24 (m, 5H), 3.18-2.97 (m, 5H), 2.89 (m, 2H), 1.75-1.66 (m, 7H),1.36 (dd, J = 12.3, 12.3 Hz, 2H). 120 2.57 11 (DMSO-d₆); δ 10.49 (m,2H), 9.50 (s, 1H), 8.70 (m, 2H), 8.18 (d, J = 9.7 Hz, TFA 1H), 7.64-7.64(m, 2H), 7.52-7.46 (m, 7H), 7.36-7.31 (m, 10H), 7.16 (d, J = 8.3 Hz,1H), 7.01-6.96 (m, 3H), 6.92 (d, J = 7.5 Hz, 1H), 6.60 (s, 1H), 6.59 (d,J = 9.8 Hz, 1H), 6.20 (s, 1H), 5.35 (d, J = 9.4 Hz, 1H), 5.11 (s, 2H),4.30-4.19 (m, 2H), 4.02-3.96 (m, 2H), 3.84-3.51 (m, 6H), 3.34-3.00 (m,10H), 2.90-2.85 (m, 2H), 1.83-1.82 (m, 3H), 1.74 (m, 2H), 1.48-1.32 (m,4H). 121 2.56 11 (DMSO-d₆); δ 10.51-10.46 (m, 2H), 9.40 (s, 1 H),8.76-8.76 (m, 2H), TFA 8.17 (d, J = 9.9 Hz, 1H), 7.51-7.47 (m, 7H),7.35-7.31 (m, 12H), 7.17 (d, J = 8.3 Hz, 1H), 7.01-6.95 (m, 3H), 6.92(d, J = 8.0 Hz, 1H), 6.65 (s, 1H), 6.60 (d, J = 9.8 Hz, 1H), 6.21-6.20(m, 1H), 5.34 (d, J = 8.0 Hz, 1H), 5.10 (s, 2H), 4.32-4.19 (m, 2H),4.10-4.10 (m, 1H), 4.03-3.96 (m, 2H), 3.63-3.62 (m, 5H), 3.34 (d, J =12.0 Hz, 4H), 3.18-2.99 (m, 6H), 2.90-2.89 (m, 4H), 1.75-1.66 (m, 7H),1.39-1.33 (m, 2H). 122 2.63 11 (DMSO-d₆) δ 10.52-10.46 (m, 2H), 9.40 (s,1H), 8.75 (s, 2H), 8.16 (d, J = 9.9 Hz, TFA 1H), 7.50-7.46 (m, 7H),7.38-7.24 (m, 12H), 7.16 (d, J = 8.3 Hz, 1H), 7.01-6.94 (m, 3H), 6.91(d, J = 7.7 Hz, 1H), 6.65 (s, 1 H), 6.60 (dd, J = 1.8, 9.9 Hz, 1H), 6.20(m, 1H), 5.33 (d, J = 8.5 Hz, 1H), 5.09 (s, 2H), 4.25 (dt, J = 5.7, 18.7Hz, 2H), 4.02-3.96 (m, 2H), 3.36-3.26 (m, 9H), 3.18 (s, 2H), 3.10-3.08(m, 2H), 3.01 (d, J = 7.9 Hz, 3H), 2.94-2.85 (m, 2H), 1.83 (s, 1H),1.75-1.65 (m, 2H), 1.50 (m, 6H), 1.34 (m, 4H).

The following compounds were prepared as described in Example 20 withthe appropriate acid replacing(R)-4-(((tert-butoxycarbonyl)(2-((tert-butyldimethylsilyl)oxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzoicacid and the use of the appropriate amine replacing tert-butyltrans-(3-aminocyclobutyl)carbamate hydrochloride in Step 1.

N Appropriate amine Appropriate acid 123

124

125

126

123

124

125

126

Salt (2 eq N Rt (min) Method NMR data (400 MHz) unless stated) 123 2.5511 (MeOD); δ 8.49 (s, 2H), 8.33 (d, J = 9.9 Hz, 1H), 7.95 (d, J = 8.4Hz, 2H), 7.87 (d, formate J = 8.3 Hz, 2H), 7.63 (d, J = 8.3 Hz, 2H),7.51 (d, J = 8.4 Hz, 2H), 7.45 (s, 5H), 7.41-7.26 (m, 7H), 7.06-6.97 (m,4H), 6.68 (d, J = 9.9 Hz, 1H), 5.42 (dd, J = 5.5, 7.7 Hz, 1H), 5.15 (s,2H), 4.70-4.61 (m, 2H), 4.31 (s, 2H), 4.11-4.06 (m, 4H), 3.29-3.18 (m,4H), 2.75-2.65 (m, 2H), 2.60 (t, J = 6.9 Hz, 4H), 1.90-1.80 (m, 1H),1.71 (d, J = 13.1 Hz, 2H), 1.45-1.33 (m, 2H). 124 2.55 11 (MeOD); δ 8.50(s, 2H), 8.29 (d, J = 9.9 Hz, 1H), 7.87 (d, J = 8.3 Hz, 2H), formate7.59-7.50 (m, 5H), 7.44 (s, 5H), 7.41-7.26 (m, 7H), 7.07-6.98 (m, 4H),6.67 (d, J = 9.8 Hz, 1H), 5.43 (dd, J = 5.6, 7.7 Hz, 1H), 5.15 (s, 2H),4.69-4.62 (m, 2H), 4.36 (s, 2H), 4.10 (d, J = 6.2 Hz, 2H), 4.05 (s, 2H),4.02 (s, 3H), 3.28-3.19 (m, 4H), 2.69-2.58 (m, 6H), 1.89-1.81 (m, 1H),1.70 (d, J = 13.1 Hz, 2H), 1.38 (q, J = 12.4 Hz, 2H). 125 2.35 11(MeOD); δ 8.53 (s, 1H), 8.29 (d, J = 10.0 Hz, 1H), 7.88 (d, J = 8.3 Hz,2H), 7.82 (d, mono-formate J = 8.4 Hz, 2H), 7.55 (d, J = 8.3 Hz, 2H),7.47 (d, J = 8.3 Hz, 2H), 7.42-7.24 (m, 12H), 7.04-6.96 (m, 4H), 6.64(d, J = 9.8 Hz, 1H), 5.36 (dd, J = 4.6, 8.7 Hz, 1H), 5.12 (s, 2H), 4.19(s, 2H), 4.06 (d, J = 6.5 Hz, 2H), 3.90 (s, 2H), 3.66 (s, 4H), 3.17-3.09(m, 4H), 2.49 (dd, J = 10.3, 12.2 Hz, 2H), 1.83-1.71 (m, 1H), 1.68-1.61(m, 2H), 1.39-1.27 (m, 2H). 126 2.54 11 (MeOD); δ 8.53 (s, 2H), 8.24 (d,J = 9.9 Hz, 1H), 7.83 (d, J = 8.3 Hz, 2H), formate 7.50-7.44 (m, 5H),7.41-7.23 (m, 12H), 7.04-6.95 (m, 4H), 6.63 (d, J = 9.8 Hz, 1H), 5.37(dd, J = 6.6, 6.6 Hz, 1H), 5.12 (s, 2H), 4.23 (s, 2H), 4.06 (d, J = 6.5Hz, 2H), 3.92 (s, 3H), 3.86 (s, 2H), 3.67 (s, 4H), 3.15-3.07 (m, 4H),2.44 (dd, J = 10.2, 12.5 Hz, 2H), 1.81-1.72 (m, 1H), 1.62 (d, J = 12.0Hz, 2H), 1.37-1.27 (m, 2H).

Example 22

(1-Benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(((1R,3S)-3-(3-hydroxy-4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-benzamido)cyclobutyl)amino)-2-oxoethoxy)phenyl)-2-phenylacetate(Compound 127)

Step 1; (1-Benzylpiperidin-4-yl)methyl(S)-2-(3-(2-(((1r,3S)-3-aminocyclobutyl)amino)-2-oxoethoxy)phenyl)-2-hydroxy-2-phenylacetatedihydrochloride

The title compound was prepared as described in Example 20 Step 1 and 2.

Step 2; (1-Benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(((1R,3S)-3-(3-hydroxy-4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-benzamido)cyclobutyl)amino)-2-oxoethoxy)phenyl)-2-phenylacetate(Compound 127)

To a solution of 4-formyl-3-hydroxybenzaldehyde (0.103 g, 0.62 mmol) andDIPEA (0.24 mL, 1.4 mmol) in DMF (2 mL) was added HATU (0.255 g, 0.67mmol) followed by a solution of (1-benzylpiperidin-4-yl)methyl(S)-2-(3-(2-(((1r,3S)-3-aminocyclobutyl)amino)-2-oxoethoxy)phenyl)-2-hydroxy-2-phenylacetatedihydrochloride (0.177 g, 0.28 mmol) in DMF (3 mL) and the reactionstirred at room temperature for 18 hours. The reaction mixture wasdissolved in ethyl acetate and washed with saturated aqueous sodiumhydrogenbicarbonate (×2) and brine. The organic phase was dried overanhydrous magnesium sulfate, filtered and the filtrate evaporated atreduced pressure. The residue was dissolved in methanol (4 mL) andtriethylamine (0.056 mL, 0.4 mmol) and(R)-5-(2-amino-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one hydrochloride(0.061 g, 0.19 mmol) added. The reaction mixture was stirred at roomtemperature for 1.5 hours then sodium triacetoxyborohydride (0.136 g,0.64 mmol) and acetic acid (0.034 mL) added. The reaction mixture wasstirred for a further 2 hours. The reaction mixture was diluted withiso-butanol and washed with water. The aqueous phase was extracted withfurther iso-butanol. The combined iso-butanol extracts were evaporatedunder reduced pressure. The residue was purified by reverse phasepreparative HPLC to afford the title compound.

The following compounds were prepared by this method or using the methoddescribed in Example 20 (using the required protected acid in the finalcoupling step).

N Preparation method as in Structure 128 Example 22

129 Example 22

130 Examaple 22

131 Example 22

132 Example 22

133 Example 22

134 Example 22

135 Example 22

136 Example 22

137 Example 22

138 Example 20

139 Example 20

140 Example 20

141 Example 20

142 Example 20

143 Example 20

144 Example 20

145 Example 20

146 Example 20

Rt Salt (2 eq N (min) Method NMR data (400 MHz) unless stated) 127 2.4511 (DMSO-d₆); δ 10.53-10.46 (m, 3H), 9.35 (s, 1H), 8.88 (s, 1H), 8.78(s, 1H), TFA 8.73 (d, J = 6.7 Hz, 1H), 8.49 (d, J = 7.4 Hz, 1H), 8.07(d, J = 9.3 Hz, 1H), 7.49 (m, 6H), 7.38-7.32 (m, 8H), 7.12 (t, J = 7.2Hz, 1H), 7.01-6.92 (m, 3H), 6.88 (dd, J = 2.3, 8.2 Hz, 1H), 6.67 (s,1H), 6.56 (dd, J = 2.0, 9.9 Hz, 1H), 6.19 (d, J = 3.8 Hz, 1H), 5.37-5.33(m, 1H), 4.43 (m, 4H), 4.30-4.24 (m, 4H), 4.02 (d, J = 6.3 Hz, 2H), 3.04(m, 4H), 2.92-2.86 (m, 2H), 2.33 (dd, J = 6.8, 6.8 Hz, 4H), 1.75 (m,3H), 1.35 (m, 2H). 128 2.43 11 (DMSO-d₆); δ 10.50 (m, 2H), 9.34 (s, 1H),9.17 (s, 2H), 8.77 (d, J = 7.3 Hz, 1H), TFA 8.50 (d, J = 7.4 Hz, 1H),8.10 (d, J = 9.6 Hz, 1H), 7.64 (dd, J = 7.7, 7.7 Hz, 1H), 7.49 (s, 6H),7.42 (d, J = 8.0 Hz, 1H), 7.34 (m, 6H), 7.14-7.10 (m, 1H), 7.01-6.93 (m,3H), 6.88 (dd, J = 2.4, 8.0 Hz, 1H), 6.66 (s, 1H), 6.60 (dd, J = 2.1,9.9 Hz, 1H), 6.21 (d, J = 2.6 Hz, 1H), 5.35 (d, J = 9.5 Hz, 1H), 4.42(s, 4H), 4.31-4.21 (m, 4H), 4.04-3.97 (m, 2H), 3.35 (d, J = 12.3 Hz,2H), 3.09-2.87 (m, 4H), 2.37-2.29 (m, 4H), 1.77-1.66 (m, 3H), 1.41-1.30(m, 2H). 129 2.43 11 (DMSO-d₆); δ 10.50 (m, 2H), 9.42 (s, 1H), 9.08 (s,2H), 8.76 (d, J = 7.2 Hz, 1H), TFA 8.51 (d, J = 7.3 Hz, 1H), 8.15 (d, J= 8.2 Hz, 1H), 7.76 (d, J = 7.3 Hz, 2H), 7.58 (d, J = 8.5 Hz, 1H), 7.48(m, 5H), 7.35-7.26 (m, 6H), 7.16 (d, J = 8.3 Hz, 1H), 7.02-6.97 (m, 2H),6.94 (d, J = 8.5 Hz, 1H), 6.89 (dd, J = 2.3, 8.0 Hz, 1H), 6.67 (s, 1H),6.59 (dd, J = 2.1, 9.9 Hz, 1H), 6.22-6.20 (m, 1H), 5.41 (d, J = 9.8 Hz,1H), 4.43 (m, 4H), 4.35-4.21 (m, 4H), 4.03 (d, J = 5.4 Hz, 2H), 3.35 (d,J = 12.2 Hz, 2H), 3.18-3.13 (m, 2H), 2.95-2.86 (m, 2H), 2.43 (s, 3H),2.34 (dd, J = 6.8, 6.8 Hz, 4H), 1.86-1.84 (m, 1H), 1.76-1.67 (m, 2H),1.36 (q, J = 12.0 Hz, 2H). 130 2.43 11 (DMSO-d₆); δ 10.53-10.47 (m, 2H),9.39 (s, 1H), 9.16 (s, 2H), 8.50 (d, J = 7.4 Hz, TFA 1H), 8.42 (d, J =7.0 Hz, 1H), 8.08 (d, J = 9.9 Hz, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.48(m, 5H), 7.37-7.24 (m, 7H), 7.16-7.11 (m, 2H), 7.02-6.93 (m, 3H), 6.89(dd, J = 8.0 Hz, 1H), 6.66 (s, 1H), 6.58 (dd, J = 2.0, 9.9 Hz, 1H),6.22-6.22 (m, 1H), 5.36 (d, J = 9.0 Hz, 1H), 4.49-4.44 (m, 1H), 4.43 (s,2H), 4.37 (dd, J = 6.7, 13.4 Hz, 1H), 4.25 (t, J = 4.7 Hz, 4H), 4.01 (d,J = 5.4 Hz, 2H), 3.89 (s, 3H), 3.34 (d, J = 9.4 Hz, 2H), 3.11-2.86 (m,4H), 2.32 (dd, J = 6.8, 6.8 Hz, 4H), 1.85-1.84 (m, 1H), 1.77-1.67 (m,2H), 1.40-1.31 (m, 2H). 131 2.47 11 (DMSO-d₆); δ 10.48 (m, 2H), 9.37 (s,1H), 8.87-8.86 (m, 2H), 8.79 (d, J = 6.9 Hz, TFA 1H), 8.52 (d, J = 7.3Hz, 1H), 8.08 (d, J = 8.4 Hz, 1H), 7.53 (m, 3H), 7.48 (m, 6H), 7.35-7.26(m, 6H), 7.13 (dd, J = 8.2, 8.2 Hz, 1H), 7.02-6.93 (m, 3H), 6.89 (dd, J= 2.4, 8.0 Hz, 1H), 6.58 (dd, J = 1.8, 9.9 Hz, 1H), 6.20 (s, 1H),5.38-5.33 (m, 1H), 4.44 (m, 4H), 4.30-4.21 (m, 4H), 4.03 (d, J = 7.0 Hz,2H), 3.97 (s, 3H), 3.33 (d, J = 11.3 Hz, 2H), 3.07 (m, 2H), 2.95-2.87(m, 2H), 2.36 (dd, J = 7.2, 7.2 Hz, 4H), 1.86-1.85 (m, 1H), 1.77-1.67(m, 2H), 1.41-1.30 (m, 2H). 132 2.46 11 (DMSO-d₆); δ 10.52-10.46 (m,2H), 9.37 (s, 1H), 9.18 (s, 2H), 8.88 (d, J = 6.9 Hz, TFA 1H), 8.51 (d,J = 7.4 Hz, 1H), 8.14 (d, J = 11.8 Hz, 1H), 7.81-7.71 (m, 3H), 7.48 (m,6H), 7.34 (m, 6H), 7.15 (d, J = 8.2 Hz, 1H), 7.02-6.93 (m, 3H), 6.89(dd, J = 2.4, 8.0 Hz, 1H), 6.59 (dd, J = 1.7, 9.9 Hz, 1H), 6.22 (s, 1H),5.38-5.36 (m, 1H), 4.43 (m, 4H), 4.36-4.21 (m, 4H), 4.05-3.97 (m, 2H),3.35 (d, J = 11.8 Hz, 2H), 3.18-3.09 (m, 2H), 2.95-2.86 (m, 2H), 2.35(dd, J = 6.8, 6.8 Hz, 4H), 1.85-1.84 (m, 1H), 1.77-1.67 (m, 2H),1.40-1.30 (m, 2H). 133 2.46 11 (MeOD); δ 8.51 (s, 2H), 8.34 (d, J = 9.9Hz, 1H), 7.55 (s, 1H), 7.47 (d, J = 7.9 Hz, Formate 1H), 7.42-7.40 (m,7H), 739-7.29 (m, 4H), 7.24 (d, J = 8.4 Hz, 1H), 7.09-7.06 (m, 2H),7.03-6.96 (m, 2H), 6.67 (d, J = 9.9 Hz, 1H), 5.31 (dd, J = 3.9, 8.9 Hz,1H), 4.53-4.45 (m, 4H), 4.13 (d, J = 6.4 Hz, 2H), 4.03 (s, 2H), 3.92 (s,2H), 3.35-3.33 (m, 2H), 3.17 (d, J = 11.9 Hz, 2H), 3.03-2.91 (m, 2H),2.53-2.43 (m, 5H), 1.88-1.80 (m, 1H), 1.69 (dd, J = 1.8, 13.6 Hz, 2H),1.43-1.30 (m, 2H) 134 2.44 11 (DMSO-d₆); δ 10.55 (d, J = 8.8 Hz, 2H),9.45-9.41 (m, 1H), 9.33-9.30 (m, 2H), TFA 8.99 (d, J = 7.1 Hz, 1H), 8.55(d, J = 7.6 Hz, 1H), 8.20 (d, J = 9.8 Hz, 1H), 7.58-7.50 (m, 6H),7.43-7.37 (m, 4H), 7.37-7.30 (m, 2H), 7.21 (d, J = 8.3 Hz, 1H),7.08-7.02 (m, 2H), 7.00 (d, J = 7.8 Hz, 1H), 6.95 (dd, J = 2.4, 8.2 Hz,1H), 6.71 (s, 1H), 6.66 (dd, J = 1.8, 9.9 Hz, 1H), 6.58 (s, 1H),6.30-6.27 (m, 1H), 5.42 (d, J = 8.8 Hz, 1H), 4.51-4.42 (m, 7H),4.38-4.27 (m, 2H), 4.08 (d, J = 6.3 Hz, 2H), 3.24-3.11 (m, 3H),3.01-2.92 (m, 2H), 2.46-2.33 (m, 4H), 1.93-1.72 (m, 3H), 1.47-1.35 (m,2H) 135 2.64 11 (DMSO-d₆); δ 10.22 (s, 1H), 8.73 (d, J = 7.1 Hz, 1H),8.41 (d, J = 7.3 Hz, 1H), mono-formate 8.10 (d, J = 8.6 Hz, 2H), 7.85(d, J = 1.8 Hz, 1H), 7.73 (dd, J = 1.6, 8.0 Hz, 1H), 7.51 (d, J = 7.8Hz, 1H), 7.28-7.16 (m, 10H), 7.00 (d, J = 8.3 Hz, 1H), 6.94 (dd, J =2.1, 2.1 Hz, 1H), 6.89-6.80 (m, 3H), 6.55 (s, 1H), 6.42 (d, J = 9.9 Hz,1H), 5.34 (s, 1H), 5.01 (dd, J = 4.7, 7.7 Hz, 1H), 4.35 (s, 4H), 3.94(d, J = 6.3 Hz, 2H), 3.80 (s, 2H), 3.33 (s, 2H), 2.72-2.59 (m, 3H), 2.27(dd, J = 6.8, 6.8 Hz, 4H), 1.81-1.73 (m, 2H), 1.50-1.36 (m, 3H),1.11-1.00 (m, 2H). 136 2.51 11 (DMSO-d₆); δ 10.51 (d, J = 12.8 Hz, 2H),9.35 (s, 1H), 9.15 (s, 2H), 8.87 (d, J = 6.8 Hz, TFA 1H), 8.49 (d, J =7.6 Hz, 1H), 8.11 (d, J = 11.2 Hz, 1H), 7.88 (d, J = 1.3 Hz, 1H), 7.58(dd, J = 1.1, 8.0 Hz, 1H), 7.52-7.47 (m, 5H), 7.38-7.24 (m, 6H),7.16-7.11 (m, 2H), 7.03-6.98 (m, 3H), 6.95 (d, J = 8.1 Hz, 1H), 6.90(dd, J = 2.4, 8.5 Hz, 1H), 6.62 (dd, J = 5.7, 5.7 Hz, 1H), 6.23 (s, 1H),5.36 (d, J = 7.6 Hz, 1H), 4.47-4.36 (m, 4H), 4.32-4.22 (m, 3H), 4.03 (d,J = 7.1 Hz, 2H), 336 (d, J = 12.8 Hz, 2H), 3.13-2.88 (m, 5H), 2.38-2.29(m, 4H), 1.90-1.82 (m, 1H), 1.78-1.66 (m, 2H), 1.41-1.33 (m, 2H). 1372.45 11 (DMSO-d₆); δ 10.52-10.50 (m, 2H), 9.39 (s, 1H), 8.93 (s, 2H),8.87 (d, J = 6.8 Hz, TFA 1H), 8.50 (d, J = 7.4 Hz, 1H), 8.12 (d, J = 9.9Hz, 1H), 7.61 (s, 1H), 7.49-7.48 (m, 5H), 7.38-7.25 (m, 6H), 7.15 (dd, J= 4.1, 4.1 Hz, 2H), 7.02-6.94 (m, 3H), 6.89 (dd, J = 2.4, 7.9 Hz, 1H),6.69 (s, 1H), 6.61 (d, J = 9.9 Hz, 1H), 6.22 (s, 1H), 5.37 (dd, J = 3.5,8.9 Hz, 1H), 4.46-4.36 (m, 4H), 4.32-4.22 (m, 4H), 4.03 (d, J = 6.4 Hz,2H), 3.88 (s, 3H), 3.34 (d, J = 11.5 Hz, 2H), 3.07-3.07 (m, 2H),2.96-2.87 (m, 2H), 2.39-2.30 (m, 4H), 1.77-1.67 (m, 3H), 1.41-1.31 (m,2H). 138 2.48 11 (DMSO-d₆); δ 10.26-10.21 (s, 1H), 8.87 (d, J = 7.1 Hz,1H), 8.43 (d, J = 7.3 Hz, 1H), formate 8.12-8.08 (m, 3H), 8.05 (d, J =8.1 Hz, 1H), 7.79 (d, J = 8.1 Hz, 1H), 7.29-7.17 (m, 11H), 7.01 (d, J =8.3 Hz, 1H), 6.95 (dd, J = 2.0, 2.0 Hz, 1H), 6.90-6.81 (m, 3H), 6.56 (s,1H), 6.42 (d, J = 9.9 Hz, 1H), 5.40 (s, 1H), 5.02 (dd, J = 4.7, 7.7 Hz,1H), 4.46-4.37 (m, 2H), 4.36 (s, 2H), 3.97-3.87 (m, 4H), 3.45 (s, 2H),2.72-2.60 (m, 4H), 2.29 (t, J = 6.8, 6.8 Hz, 4H), 1.83-1.73 (t, 2H),1.49-1.37 (m, 3H), 1.12-1.00 (m, 2H). 139 2.43 11 (DMSO-d₆); δ 10.51 (s,2H), 9.40 (s, 1H), 9.04-9.04 (m, 2H), 8.83 (d, J = 6.9 Hz, TFA 1H), 8.51(d, J = 7.4 Hz, 1H), 8.13 (d, J = 9.8 Hz, 1H), 7.49-7.48 (m, 5H),7.42-7.24 (m, 8H), 7.15 (d, J = 8.3 Hz, 1H), 7.02-6.93 (m, 3H), 6.89(dd, J = 2.4, 8.1 Hz, 1H), 6.67 (s, 1H), 6.60 (d, J = 9.9 Hz, 1H), 6.23(s, 1H), 5.38 (dd, J = 3.0, 9.3 Hz, 1H), 4.48-4.38 (m, 4H), 4.36-4.26(m, 4H), 4.04 (d, J = 5.2 Hz, 2H), 3.96 (d, J = 2.0 Hz, 3H), 3.34 (d, J= 11.5 Hz, 2H), 3.15-3.05 (m, 2H), 2.96-2.87 (m, 2H), 2.38-2.29 (m, 4H),1.84-1.66 (m, 3H), 1.41-1.31 (m, 2H). 140 2.46 11 (MeOD); δ 8.54 (s,1H), 8.29 (d, J = 9.9 Hz, 1H), 7.49 (d, J = 6.7 Hz, 2H), mono-formate7.46-7.31 (m, 12H), 7.24 (d, J = 8.3 Hz, 1H), 7.11-7.07 (m, 2H),7.04-6.98 (m, 2H), 6.64 (d, J = 9.9 Hz, 1H), 5.36-5.31 (m, 1H),4.59-4.48 (m, 4H), 4.23-4.17 (m, 4H), 4.12 (d, J = 6.9 Hz, 2H), 3.79 (s,2H), 3.13-3.04 (m, 4H), 2.53-2.46 (m, 4H), 2.36 (dd, J = 11.6, 11.6 Hz,2H), 1.82-1.74 (m, 1H), 1.67-1.64 (m, 2H), 1.46 (dd, J = 7.0, 7.0 Hz,3H), 1.39-1.29 (m, 2H). 141 2.49 11 (MeOD); δ 8.50 (s, 1H), 8.34 (d, J =9.9 Hz, 1H), 7.87 (dd, J = 1.6, 7.9 Hz, 1H), mono-formate 7.83-7.82 (m,1H), 7.67 (d, J = 8.0 Hz, 1H), 7.45-7.40 (m, 7H), 7.39-7.30 (m, 4H),7.24 (d, J = 8.2 Hz, 1H), 7.10-7.08 (m, 2H), 7.03-6.98 (m, 2H), 6.64 (d,J = 9.8 Hz, 1H), 5.28 (dd, J = 4.3, 8.4 Hz, 1H), 4.60-4.45 (m, 4H), 4.14(d, J = 6.3 Hz, 2H), 4.04 (s, 2H), 3.97 (s, 2H), 3.21 (d, J = 12.6 Hz,2H), 3.00-2.88 (m, 2H), 2.64-2.57 (m, 2H), 2.53-2.44 (m, 4H), 1.91-1.83(m, 1H), 1.74-1.70 (m, 2H), 1.44-1.33 (m, 2H). 142 2.47 11 (MeOD); δ8.49 (s, 2H), 8.32 (d, J = 9.9 Hz, 1H), 7.45-7.40 (m, 7H), 7.39-7.25 (m,formate 7H), 7.10-7.07 (m, 2H), 7.04 (d, J = 8.2 Hz, 1H), 7.01-6.97 (m,1H), 6.68 (d, J = 9.9 Hz, 1H), 5.40-5.35 (m, 1H), 4.60-4.45 (m, 4H),4.18 (s, 2H), 4.15 (d, J = 6.2 Hz, 2H), 4.02 (s, 2H), 3.93 (s, 3H), 3.24(d, J = 12.0 Hz, 2H), 3.12 (d, J = 6.1 Hz, 2H), 2.65 (dd, J = 11.5, 13.1Hz, 2H), 2.48 (dd, J = 6.9, 6.9 Hz, 4H), 1.89-1.84 (m, 1H), 1.73 (d, J =12.0 Hz, 2H), 1.47-1.33 (m, 2H) 143 2.52 11 (MeOD); δ 8.50 (s, 2H), 8.29(d, J = 9.9 Hz, 1H), 7.54 (s, 1H), 7.51-7.47 (m, 2H), formate 7.44-7.40(m, 7H), 7.39-7.30 (m, 4H)), 7.26 (d, J = 8.3 Hz, 1H), 7.11-7.07 (m,2H), 7.04 (d, J = 7.9 Hz, 1H), 7.01-6.97 (m, 1H), 6.66 (d, J = 9.9 Hz,1H), 5.37 (dd, J = 4.6, 8.7 Hz, 1H), 4.87-4.82 (m, 1H), 4.61-4.46 (m,4H), 4.26 (d, J = 2.8 Hz, 2H), 4.14 (d, J = 6.4 Hz, 2H), 3.96 (s, 2H),3.24-3.17 (m, 4H), 2.61-2.46 (m, 6H), 1.90-1.83 (m, 1H), 1.76-1.70 (m,2H), 1.45-1.32 (m, 8H). 144 2.46 11 (MeOD); δ 8.71 (d, J = 1.5 Hz, 1H),8.45 (s, 2H), 8.35 (d, J = 9.9 Hz, 1H), 8.10 (d, formate J = 8.0 Hz,1H), 8.03 (dd, J = 2.0, 8.2 Hz, 1H), 7.48-7.41 (m, 7H), 7.39-7.31 (m,4H), 7.27 (d, J = 7.6 Hz, 1H), 7.11-7.07 (m, 2H), 7.05-6.98 (m, 2H),6.66 (d, J = 9.9 Hz, 1H), 5.35 (dd, J = 4.3, 8.7 Hz, 1H), 4.65-4.57 (m,1H), 4.51 (s, 2H), 4.50-4.43 (m, 1H), 4.18-4.13 (m, 4H), 4.11 (s, 2H),3.34-3.27 (m, 2H), 3.11-3.06 (m, 2H), 2.80-2.74 (m, 2H), 2.59-2.45 (m,4H), 1.94-1.88 (m, 1H), 1.76 (d, J = 14.2 Hz, 2H), 1.49-1.36 (m, 2H).145 2.44 11 (MeOD); δ 9.12 (d, J = 1.8 Hz, 1H), 9.02 (d, J = 5.5 Hz,1H), 8.56 (d, J = 7.6 Hz, 1H), TFA 8.39 (d, J = 9.9 Hz, 1H), 8.31 (dd, J= 2.2, 8.2 Hz, 1H), 7.59 (d, J = 8.3 Hz, 1H), 7.52-7.51 (m, 5H),7.43-7.32 (m, 7H), 7.11-7.05 (m, 3H), 7.00 (dd, J = 2.1, 7.2 Hz, 1H),6.71 (d, J = 9.8 Hz, 1H), 5.55 (dd, J = 5.2, 8.2 Hz, 1H), 4.63-4.48 (m,6H), 4.29 (s, 2H), 4.14 (d, J = 6.3 Hz, 2H), 3.52-3.42 (m, 2H),3.41-3.36 (m, 2H), 2.99 (dd, J = 10.6, 13.2 Hz, 2H), 2.50 (dd, J = 6.8,6.8 Hz, 4H), 2.02-1.96 (m, 1H), 1.84 (d, J = 14.7 Hz, 2H), 1.49-1.39 (m,2H) 146 2.49 11 (MeOD); δ 8.52 (s, 1H), 8.26 (d, J = 9.9 Hz, 1H),7.47-7.43 (m, 2H), 7.42-7.38 (m, mono-formate 9H), 7.37-7.25 (m, 5H),7.09-7.06 (m, 2H), 7.03 (d, J = 8.2 Hz, 1H), 6.99-6.96 (m, 1H), 6.66 (d,J = 9.9 Hz, 1H), 5.37 (dd, J = 4.7, 8.7 Hz, 1H), 4.49-4.41 (m, 3H),4.34-4.25 (m, 1H), 4.22 (s, 2H), 4.12 (d, J = 6.4 Hz, 2H), 3.90 (s, 2H),3.56 (s, 2H), 3.18-3.13 (m, 4H), 2.50 (dd, J = 11.5, 11.5 Hz, 2H),2.42-2.27 (m, 4H), 1.86-1.78 (m, 1H), 1.68 (d, J = 12.2 Hz, 2H),1.42-1.30 (m, 2H)

Example 23

(1-Benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(3-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)piperidine-1-carbonyl)azetidin-1-yl)-2-oxoethoxy)phenyl)-2-phenylacetate(Compound 147)

Step 1; Benzyl(R)-3-(4-(((tert-butoxycarbonyl)(2-((tert-butyldimethylsilyl)oxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)piperidine-1-carbonyl)azetidine-1-carboxylate

To a solution of 1-((benzyloxy)carbonyl)azetidine-3-carboxylic acid(0.306 g, 1.3 mmol) and DIPEA (0.266 mL, 1.3 mmol) in DMF (10 mL) wasadded HATU (0.494 g, 0.494 g, 1.3 mmol) and the reaction mixture stirredat room temperature for 30 minutes. (R)-Tert-butyl(2-((tert-butyldimethylsilyl)oxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)(piperidin-4-ylmethyl)carbamate(0.531 g, 1.0 mmol) was added and the mixture stirred for a further 18hours. The mixture was diluted with ethyl acetate and washed with water,10% aqueous potassium carbonate and brine (×2). The organic phase wasdried over anhydrous magnesium sulfate, filtered and the filtrateevaporated at reduced pressure to afford the title compound (0.759 g,100%).

LCMS Method 11; Rt 3.80 min; ES⁺749.6.

Step 2; tert-Butyl(R)-((1-(azetidine-3-carbonyl)piperidin-4-yl)methyl)(2-((tert-butyldimethylsilyl)oxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)carbamate

To a solution of benzyl(R)-3-(4-(((tert-butoxycarbonyl)(2-((tert-butyldimethyl-silyl)oxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)piperidine-1-carbonyl)azetidine-1-carboxylate(0.759 g, 1.0 mmol) in ethanol (10 mL) was added 10% palladium on carbon(0.8 g) and 1-methyl-1,4-cyclohexadiene (0.562 mL). The reaction mixturewas heated to reflux and heated at reflux for one hour. The suspensionwas filtered and the filtrate evaporated at reduced pressure to affordthe title compound (0.516 g, 84%).

LCMS Method 11; Rt 3.02 min; ES⁺615.

Step 3; (1-Benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(3-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)piperidine-1-carbonyl)azetidin-1-yl)-2-oxoethoxy)phenyl)-2-phenylacetate(Compound 147)

To a stirred solution of tert-butyl(R)-((1-(azetidine-3-carbonyl)piperidin-4-yl)methyl)(2-((tert-butyldimethylsilyl)oxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)carbamate(0250 g, 0.41 mmol) and(S)-2-(3-(2-((1-benzylpiperidin-4-yl)methoxy)-1-hydroxy-2-oxo-1-phenylethyl)phenoxy)aceticacid hydrochloride (0.235 g, 0.45 mmol) in DMF (3 mL) was added EDC(0.11 g, 0.57 mmol), HOBt (0.078 g, 0.58 mmol) and 4-DMAP (catalytic).The reaction mixture was stirred at room temperature for 72 hours. Thereaction mixture was diluted with ethyl acetate and washed with water,10% aqueous potassium carbonate and brine (×2). The organic phase wasdried over anhydrous magnesium sulfate, filtered and the filtrateevaporated at reduced pressure. The residue was dissolved in MeCN (2 mL)and a solution of HCl-dioxan (4 mL) added. The reaction mixture wasstirred at room temperature for 1 hour. The solvent was evaporated atreduced pressure and the residue purified by reverse preparative HPLC.

The following compounds were prepared by this method:

N Structure 147

148

149

150

Rt Salt N (min) Method NMR data (400 MHz) (2 eq unless stated) 147 2.4011 (MeOD); δ 8.43-8.38 (m, 1H), 7.54-7.48 (m, 6H), 7.41-7.28 (m, 6H),TFA 7.10-7.05 (m, 2H), 7.00-6.98 (m, 1H), 6.93 (dd, J = 2.3, 8.1 Hz,1H), 6.73-6.68 (m, 1H), 5.46 (dd, J = 5.6, 8.0 Hz, 1H), 4.61 (d, J = 4.1Hz, 3H), 4.53-4.40 (m, 2H), 4.29 (s, 2H), 4.26-4.16 (m, 1H), 4.14 (d, J= 6.0 Hz, 3H), 3.89-3.80 (m, 1H), 3.72 (d, J = 14.6 Hz, 1H), 3.52-3.45(m, 2H), 3.29 (d, J = 7.2 Hz, 2H), 3.19-2.95 (m, 6H), 2.76 (dd, J =12.7, 12.7 Hz, 1H), 2.13-2.09 (m, 1H), 2.02-1.72 (m, 4H), 1.42 (dd, J =12.9, 12.9 Hz, 2H), 1.32-1.24 (m, 2H). 148 2.40 11 (MeOD); δ 8.40 (d, J= 9.9 Hz, 1H), 7.54-7.47 (m, 6H), 7.42-7.25 (m, 6H), TFA 7.06 (d, J =8.2 Hz, 2H), 6.99 (s, 1H), 6.92 (dd, J = 2.1, 8.3 Hz, 1H), 6.71 (d, J =9.9 Hz, 1H), 5.46 (t, J = 7.3 Hz, 1H), 4.83-4.72 (m, 3H), 4.61 (d, J =14.6 Hz, 1H), 4.49-4.33 (m, 1H), 4.28 (s, 2H), 4.20-4.10 (m, 3H), 3.98(d, J = 15.6 Hz, 1H), 3.51-3.42 (m, 2H), 3.30-3.15 (m, 5H), 3.10-2.94(m, 5H), 2.82 (t, J = 11.9 Hz, 1H), 2.70 (t, J = 11.9 Hz, 1H), 2.14-2.10(m, 1H), 1.98-1.93 (m, 2H), 1.84-1.78 (m, 4H), 1.70-1.55 (m, 1H),1.46-1.20 (m, 4H). 149 2.43 11 (MeOD) d 8.41 (d, J = 9.8 Hz, 1H), 7.95(d, J = 6.6 Hz, 1H), 7.51 (s, 5H), TFA 7.40-7.27 (m, 6H), 7.11-7.05 (m,2H), 7.01 (s, 1H), 6.96 (dd, J = 2.1, 8.0 Hz, 1H), 6.71 (d, J = 9.9 Hz,1H), 5.45 (t, J = 6.4 Hz, 1H), 4.61 (d, J = 13.6 Hz, 1H), 4.47 (s, 2H),4.28 (s, 2H), 4.17-4.08 (m, 3H), 3.72-3.67 (m, 1H), 3.50-3.43 (m, 2H),3.28 (d, J = 7.3 Hz, 2H), 3.21-3.13 (m, 2H), 3.10-2.93 (m, 5H),2.71-2.62 (m, 2H), 2.13-2.09 (m, 1H), 1.97-1.91 (m, 4H), 1.86-1.76 (m,4H), 1.64-1.47 (m, 2H), 1.43-1.19 (m, 6H). 150 2.42 11 (MeOD); δ 8.40(d, J = 9.9 Hz, 1H), 7.53-7.48 (m, 5H), 7.42-7.29 (m, 7H), TFA 7.11-7.04(m, 3H), 7.00 (dd, J = 2.3, 8.1 Hz, 1H), 6.71 (d, J = 9.8 Hz, 1H), 5.45(dd, J = 6.0, 7.8 Hz, 1H), 4.59-4.53 (m, 3H), 4.28 (s, 2H), 4.25-4.09(m, 4H), 3.96 (d, J = 13.2 Hz, 1H), 3.51-3.45 (m, 2H), 3.28 (d, J = 7.8Hz, 2H), 3.21-3.14 (m, 2H), 3.09-2.94 (m, 4H), 2.74 (t, J = 13.2 Hz,1H), 2.15-2.08 (m, 1H), 1.99-1.80 (m, 5H), 1.47-1.20 (m, 3H).

Example 24

(1-Benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-((1-(1-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzoyl)piperidine-4-carbonyl)piperidin-4-yl)methoxy)phenyl)-2-phenylacetate(Compound 151)

The title compound was prepared using a similar route to that describedin Example 22 using previously described compounds (see Proceduressection). An acidic deprotection step (as described in Example 20 Step2) was utilized prior to the final coupling step.

The following compounds were prepared by this method;

N Structure 152

153

154

155

Rt Salt N (min) Method NMR data (400 MHz) (2 eq unless stated) 151 2.5511 (DMSO-d₆, 90° C.); δ 8.20 (d, J = 9.9 Hz, 1H), 7.49-7.43 (m, 5H),7.35 (dd, J = 7.6, TFA 7.6 Hz, 9H), 7.27-7.21 (m, 1H), 7.16 (d, J = 8.3Hz, 1H), 7.02 (d, J = 8.2 Hz, 1H), 6.96-6.92 (m, 2H), 6.89-6.86 (m, 1H),6.57 (d, J = 9.9 Hz, 1H), 5.38 (dd, J = 4.3, 8.6 Hz, 1H), 4.19-4.19 (m,4H), 4.11-3.97 (m, 3H), 3.82 (d, J = 6.3 Hz, 2H), 3.31 (t, J = 8.2 Hz,2H), 3.28-3.08 (m, 9H), 3.01-2.75 (m, 5H), 2.02-1.97 (m, 1H), 1.81-1.53(m, 11H), 1.28-1.18 (m, 2H). 152 2.53 11 (MeOD); δ 8.50 (s, 1H), 8.37(d, J = 9.9 Hz, 1H), 7.88 (d, J = 8.3 Hz, 2H), mono-formate 7.44-7.33(m, 12H), 7.32-7.24 (m, 2H), 7.04 (d, J = 8.2 Hz, 1H), 7.03-6.98 (m,2H), 6.90 (dd, J = 2.1, 7.9 Hz, 1H), 6.70 (d, J = 9.8 Hz, 1H), 5.39 (dd,J = 4.8, 8.7 Hz, 1H), 4.57 (d, J = 12.2 Hz, 1H), 4.29 (dd, J = 15.6,38.7 Hz, 2H), 4.12 (d, J = 6.7 Hz, 2H), 4.01 (d, J = 13.4 Hz, 1H), 3.92(s, 2H), 3.84 (d, J = 6.0 Hz, 2H), 3.28-3.07 (m, 9H), 2.79-2.67 (m, 1H),2.52-2.52 (m, 2H), 2.12-2.06 (m, 1H), 1.95-1.79 (m, 3H), 1.70 (d, J =13.6 Hz, 2H), 1.48-1.28 (m, 4H). 153 2.53 11 ¹H NMR (400 MHz, MeOD) d8.40 (s, 2H), 8.14 (d, J = 9.9 Hz, 1H), 7.41 (s, 1H), formate 7.39-7.35(m, 1H), 7.32-7.19 (m, 11H), 7.14-7.08 (m, 2H), 6.89-6.82 (m, 3H),6.77-6.74 (m, 1H), 6.51 (d, J = 9.9 Hz, 1H), 5.20 (dd, J = 5.3, 7.8 Hz,1H), 4.43 (d, J = 12.8 Hz, 1H), 4.24-4.08 (m, 2H), 4.04 (s, 2H),3.98-3.85 (m, 3H), 3.81 (s, 3H), 3.70 (d, J = 6.0 Hz, 2H), 3.58 (s, 2H),3.03-2.84 (m, 5H), 2.66-2.53 (m, 1H), 2.13 (dd, J = 11.5, 11.5 Hz, 2H),1.96-1.91 (m, 1H), 1.83-1.70 (m, 2H), 1.63-1.54 (m, 1H), 1.48 (d, J =13.3 Hz, 2H), 1.36-1.24 (m, 1H), 1.17 (q, J = 12.5 Hz, 3H). 154 2.50 11(MeOD); δ 8.48 (s, 2H), 8.32 (d, J = 9.9 Hz, 1H), 7.97 (d, J = 8.3 Hz,2H), 7.62 (d, formate J = 8.3 Hz, 2H), 7.45 (s, 5H), 7.43-7.34 (m, 5H),7.27 (dd, J = 7.8, 7.8 Hz, 2H), 7.04 (d, J = 8.2 Hz, 1H), 6.99 (d, J =2.3 Hz, 2H), 6.91 (dd, J = 1.9, 8.2 Hz, 1H), 6.67 (d, J = 9.8 Hz, 1H),5.44-5.39 (m, 1H), 4.61-4.60 (m, 1H), 4.35-4.27 (m, 4H), 4.16-4.08 (m,4H), 4.02 (d, J = 13.7 Hz, 1H), 3.85 (d, J = 6.0 Hz, 2H), 3.28 (d, J =12.3 Hz, 2H), 3.20 (d, J = 7.4 Hz, 3H), 2.79-2.68 (m, 4H), 2.11-2.06 (m,1H), 1.96-1.86 (m, 2H), 1.76 (d, J = 13.2 Hz, 2H), 1.51-1.39 (m, 3H),1.37-1.26 (m, 1H). 155 2.52 11 (DMSO-d₆); d 10.50 (s, 2H), 9.44-9.44 (m,1H), 9.20-9.20 (m, 2H), 8.74 (dd, TFA J = 4.3, 4.3 Hz, 1H), 8.10 (d, J =9.9 Hz, 1H), 7.98 (d, J = 7.9 Hz, 1H), 7.48 (s, 5H), 7.42 (s, 1H), 7.34(d, J = 3.8 Hz, 4H), 7.32-7.21 (m, 3H), 7.14 (d, J = 8.3 Hz, 1H), 6.99(d, J = 8.2 Hz, 1H), 6.89 (d, J = 7.8 Hz, 3H), 6.64 (s, 1H), 6.58 (d, J= 9.9 Hz, 1H), 6.34-6.12 (m, 1H), 5.39-5.35 (m, 1H), 4.44 (d, J = 12.5Hz, 1H), 4.31-4.19 (m, 4H), 4.02 (d, J = 6.4 Hz, 2H), 3.86-3.77 (m, 4H),3.34 (d, J = 11.8 Hz, 2H), 3.11-3.01 (m, 4H), 2.96-2.87 (m, 2H),2.70-2.64 (m, 1H), 2.03-2.00 (m, 1H), 1.82-1.67 (m, 6H), 1.42-1.24 (m,3H), 1.20-1.11 (m, 1H).

Example 25

(1-Benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-((1-(5-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)piperidine-1-carbonyl)thiophene-2-carbonyl)piperidin-4-yl)methoxy)phenyl)-2-phenylacetate(Compound 156)

The title compound was prepared using a similar route to that describedin Example 23 using previously described compounds (see Proceduressection). A base promoted deprotection step (as described in Example 1Step 4) was utilized prior to the final coupling step.

The following compounds were prepared by this method:

N Structure 157

Rt Salt N (min) Method NMR data (400 MHz) (2 eq unless stated) 156 2.5311 (MeOD); δ 8.53 (s, 1H), 8.41 (d, J = 9.9 Hz, 1H), 7.40-7.25 (m, 14H),7.05 (d, mono-formate J = 8.2 Hz, 1H), 6.99-6.97 (m, 2H), 6.90 (dd, J =2.1, 8.0 Hz, 1H), 6.70 (d, J = 9.8 Hz, 1H), 5.42 (dd, J = 5.0, 8.5 Hz,1H), 4.44 (s, 4H), 4.11 (dd, J = 2.8, 6.4 Hz, 2H), 3.87-3.81 (m, 4H),3.23-3.05 (m, 7H), 3.00 (d, J = 6.9 Hz, 3H), 2.39 (t, J = 12.9 Hz, 2H),2.15-2.09 (m, 2H), 1.98-1.88 (m, 4H), 1.80-1.74 (m, 1H), 1.67 (d, J =12.8 Hz, 2H), 1.45-1.29 (m, 6H). 157 2.55 11 (DMSO-d₆, 100° C.); δ 8.20(d, J = 9.9 Hz, 1H), 7.48-7.46 (m, 5H), 7.41-7.21 (m, TFA 6H), 7.16 (d,J = 8.3 Hz, 1H), 7.02 (d, J = 8.2 Hz, 1H), 6.97-6.93 (m, 2H), 6.89-6.86(m, 1H), 6.58 (d, J = 9.9 Hz, 1H), 5.38 (dd, J = 4.8, 8.2 Hz, 1H),4.26-4.06 (m, 8H), 3.83 (d, J = 6.3 Hz, 2H), 3.20-3.14 (m, 2H),3.01-2.98 (m, 2H), 2.93-2.76 (m, 7H), 2.61-2.60 (m, 2H), 2.10-1.99 (m,2H), 1.80-1.69 (m, 12H), 1.62-1.48 (m, 6H), 1.29-1.11 (m, 4H).

Example 26

1-Benzylpiperidin-4-yl(S)-2-hydroxy-2-(3-(3-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzamido)propoxy)phenyl)-2-phenylacetate(Compound 158)

Step 1; Methyl(S)-2-(3-(3-((tert-butoxycarbonyl)amino)propoxy)phenyl)-2-hydroxy-2-phenylacetate

To a stirred solution of methyl(S)-2-hydroxy-2-(3-hydroxyphenyl)-2-phenylacetic acid (3.0 g, 11.62mmol) in DMF (11 mL) was added potassium carbonate (3.21 g, 23.23 mmol)followed by a solution of tert-butyl (3-bromopropyl)carbamate (3.46 g,14.52 mmol) in DMF (11 mL). The reaction mixture was heated at 60° C.for 18 hours. The reaction mixture was dissolved in ethyl acetate andwashed with aqueous 1M sodium hydroxide (×2), water and brine. Theorganic phase was dried over anhydrous magnesium sulfate, filtered andthe filtrate evaporated at reduced pressure. The residue was purified byflash column chromatography (eluent 100% i-hexane to 60% ethylacetate/i-hexane) to afford the title compound (4.71 g, 98%).

¹H NMR (400 MHz, DMSO-d₆); δ 7.38-7.27 (m, 6H), 6.95-6.88 (m, 4H), 6.70(s, 1H), 3.96 (dd, J=6.3, 6.3 Hz, 2H), 3.77 (s, 3H), 3.11 (q, J=6.5 Hz,2H), 1.90-1.81 (m, 2H), 1.42 (s, 9H).

Step 2;(S)-2-(3-(3-((tert-Butoxycarbonyl)amino)propoxy)phenyl)-2-hydroxy-2-phenylaceticacid

To a stirred solution of methyl(S)-2-(3-(3-((tert-butoxycarbonyl)amino)propoxy)-phenyl)-2-hydroxy-2-phenylacetate(4.71 g, 11.34 mmol) in THF/methanol (57 mL/57 mL) was added aqueous 2Msodium hydroxide (57 mL). The reaction mixture was stirred at roomtemperature for 18 hours. The solvent was concentrated under reducedpressure to ⅓ volume. The solution was washed with ether and the pHadjusted to pH2 and the solution was extracted with ethyl acetate. Theorganic phase was dried over anhydrous magnesium sulfate, filtered andthe filtrate evaporated at reduced pressure to afford the title compound(4.1 g, 90%).

¹H NMR (400 MHz, DMSO-d₆); δ 7.45-7.41 (m, 2H), 7.39-7.26 (m, 4H),7.01-6.96 (m, 2H), 6.94-6.87 (m, 2H), 6.37 (br s), 3.96 (dd, J=6.3, 6.3Hz, 2H), 3.14-3.07 (m, 2H), 1.89-1.81 (m, 2H), 1.42 (s, 9H).

Step 3; 1-Benzylpiperidin-4-yl(S)-2-(3-(3-aminopropoxy)phenyl)-2-hydroxy-2-phenylacetatedihydrochloride

Carbonyldiimidazole (0.242 g, 1.50 mmol) was added to a solution of(S)-2-(3-(3-((tert-butoxycarbonyl)amino)propoxy)phenyl)-2-hydroxy-2-phenylaceticacid (0.20 g, 0.5 mmol) in DMF (2 mL) and the mixture stirred at roomtemperature for 15 mins. 1-Benzylpiperidin-4-ol (0.381 g, 1.99 mmol) inDMF (0.5 mL) was added and the reaction mixture heated at 60° C. for 18hours. The reaction mixture was diluted with ethyl acetate and washedwith saturated aqueous sodium carbonate (×2) and brine. The organicphase was dried over anhydrous magnesium sulfate, filtered and thefiltrate evaporated at reduced pressure. The residue was purified byflash column chromatography (eluent 100% DCM to 5% MeOH/DCM) to affordmajor product. This material was dissolved in dioxane (1 mL) and asolution of 4M HCl in dioxane (2 mL) added. The reaction mixture stirredat room temperature for 1.5 hours. The solvent was evaporated at reducedpressure to afford the title compound (0.157 g, 57%).

LCMS Method 11; Rt 2.35; ES⁺475.

Step 4; 1-Benzylpiperidin-4-yl(S)-2-hydroxy-2-(3-(3-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzamido)propoxy)phenyl)-2-phenylacetate(Compound 158)

The title compound was prepared as described in Example 5.

The following compounds were prepared according to Example 26:

N Structure 159

160

161

162

163

164

165

Salt N Rt (min) Method NMR data (400 MHz) (2 eq unless stated) 158 2.4211 (MeOD); δ 8.44 (s, 2H), 8.30 (d, J = 9.9 Hz, 1H), 7.89 (d, J = 8.2Hz, 2H), formate 7.60 (d, J = 8.2 Hz, 2H), 7.45-7.34 (m, 10H), 7.29 (dd,J = 8.1, 8.1 Hz, 2H), 7.05-6.93 (m, 4H), 6.66 (d, J = 9.8 Hz, 1H), 5.42(t, J = 6.6 Hz, 1H), 5.12-5.04 (m, 1H), 4.33 (s, 2H), 4.09 (t, J = 6.0Hz, 2H), 3.82 (s, 2H), 3.59 (t, J = 6.8 Hz, 2H), 3.21 (d, J = 6.7 Hz,2H), 2.85-2.76 (m, 2H), 2.62-2.62 (m, 2H), 2.16-2.07 (m, 2H), 2.01-1.96(m, 2H), 1.90-1.82 (m, 2H). 159 2.44 11 (DMSO-d₆); δ 10.54 (m, 2H),9.96-9.96 (m, 1H), 9.18 (s, 2H), 8.66 (dd, TFA J = 5.4, 5.4 Hz, 1H),8.13 (d, J = 8.9 Hz, 1H), 7.95 (d, J = 8.1 Hz, 2H), 7.66 (d, J = 8.1 Hz,2H), 7.52 (d, J = 5.3 Hz, 6H), 7.41-7.38 (m, 2H), 7.36 (s, 3H),7.33-7.25 (m, 1H), 7.18 (d, J = 8.3 Hz, 1H), 7.03 (d, J = 8.1 Hz, 1H),6.97-6.91 (m, 3H), 6.63 (d, J = 9.9 Hz, 1H), 6.25 (s, 1H), 5.39 (d, J =7.8 Hz, 1H), 4.43-4.15 (m, 6H), 4.07-4.02 (m, 3H), 3.47-3.47 (m, 4H),3.17-3.02 (m, 3H), 2.88-2.73 (m, 1H), 2.19-2.19 (m, 1H), 2.06-1.98 (m,2H), 1.84-1.76 (m, 1H). 160 2.44 11 (DMSO-d₆); δ 10.54 (m, 2H), 10.01(s, 1H), 9.18 (s, 2H), 8.66 (dd, J = 5.6, 5.6 Hz, TFA 1H), 8.13 (d, J =9.9 Hz, 1H), 7.95 (d, J = 8.1 Hz, 2H), 7.66 (d, J = 8.3 Hz, 2H), 7.52(m, 5H), 7.40-7.34 (m, 5H), 7.30 (dd, J = 8.0, 8.0 Hz, 1H), 7.18 (d, J =8.1 Hz, 1H), 7.03 (d, J = 8.1 Hz, 1H), 6.98-6.90 (m, 3H), 6.78-6.71 (m,1H), 6.63 (d, J = 9.9 Hz, 1H), 6.24 (s, 1H), 5.40 (d, J = 9.3 Hz, 1H),4.41-4.15 (m, 7H), 4.08-4.01 (m, 2H), 3.48 (dd, J = 6.9, 11.1 Hz, 4H),3.17-3.05 (m, 4H), 2.87-2.77 (m, 1H), 2.06-1.98 (m, 2H), 1.83-1.74 (m,1H). 161 2.41 11 (DMSO-d₆); δ 8.54-8.47 (m, 1H), 8.20 (s, 2H), 8.13 (dd,J = 3.1, 9.2 Hz, 1H), formate 7.79 (d, J = 8.3 Hz, 2H), 7.41 (d, J = 8.3Hz, 2H), 7.33 (d, J = 4.4 Hz, 4H), 7.32-7.22 (m, 2H), 7.07 (d, J = 8.2Hz, 1H), 6.94-6.87 (m, 4H), 6.48 (d, J = 9.8 Hz, 1H), 5.10 (dd, J = 4.3,8.0 Hz, 1H), 3.99 (dd, J = 4.0, 5.9 Hz, 4H), 3.84 (s, 2H), 3.40 (td, J =7.6, 19.3 Hz, 2H), 2.77-2.61 (m, 5H), 1.99-1.88 (m, 4H), 1.77-1.47 (m,9H), 1.14-1.05 (m, 2H). 162 2.46 11 (DMSO-d₆); δ 8.50 (t, J = 7.1 Hz,1H), 8.22 (s, 2H), 8.13 (d, J = 9.9 Hz, 1H), formate 7.79 (d, J = 8.2Hz, 2H), 7.41 (d, J = 8.3 Hz, 2H), 7.33 (d, J = 4.4 Hz, 4H), 7.32-7.22(m, 2H), 7.07 (d, J = 8.2 Hz, 1H), 6.94-6.87 (m, 4H), 6.48 (d, J = 9.9Hz, 1H), 5.10 (dd, J = 4.3, 8.0 Hz, 1H), 4.02-3.96 (m, 4H), 3.83 (s,2H), 3.44-3.37 (m, 2H), 2.79-2.64 (m, 4H), 2.17 (s, 3H), 1.99-1.87 (m,4H), 1.53-1.45 (m, 3H), 1.21-1.10 (m, 2H). 163 2.41 11 (MeOD); δ 8.43(s, 2H), 8.30 (d, J = 9.8 Hz, 1H), 7.90 (d, J = 8.3 Hz, 2H), formate7.61 (d, J = 8.3 Hz, 2H), 7.43 (dd, J = 1.7, 8.0 Hz, 2H), 7.38-7.24 (m,10H), 7.05-6.99 (m, 3H), 6.92 (dd, J = 2.0, 8.2 Hz, 1H), 6.66 (d, J =9.9 Hz, 1H), 5.46-5.39 (m, 2H), 4.34 (s, 2H), 4.06 (dd, J = 6.0, 6.0 Hz,2H), 3.90-3.77 (m, 2H), 3.58 (dd, J = 6.8, 6.8 Hz, 2H), 3.22 (d, J = 6.7Hz, 2H), 3.15 (dd, J = 5.5, 12.4 Hz, 1H), 3.01-2.82 (m, 3H), 2.38-2.28(m, 1H), 2.10 (ddd, J = 8.2, 8.2, 8.2 Hz, 2H), 2.00-1.93 (m, 1H). 1642.41 11 (MeOD); δ 8.43 (s, 2H), 8.30 (d, J = 9.8 Hz, 1H), 7.90 (d, J =8.2 Hz, 2H), formate 7.61 (d, J = 8.2 Hz, 2H), 7.44-7.24 (m, 12H),7.05-7.00 (m, 3H), 6.92 (dd, J = 2.3, 8.3 Hz, 1H), 6.66 (d, J = 9.8 Hz,1H), 5.41 (q, J = 6.5 Hz, 2H), 4.33 (s, 2H), 4.06 (dd, J = 6.0, 6.0 Hz,2H), 3.81 (q, J = 12.5 Hz, 2H), 3.58 (dd, J = 6.8, 6.8 Hz, 2H), 3.22 (d,J = 6.7 Hz, 2H), 3.13 (dd, J = 5.7, 12.5 Hz, 1H), 2.97-2.88 (m, 2H),2.88-2.79 (m, 1H), 2.38-2.27 (m, 1H), 2.14-2.06 (m, 2H), 1.98-1.91 (m,1H). 165 2.41 11 (MeOD); δ 8.46 (s, 2H), 8.31 (d, J = 9.9 Hz, 1H), 7.89(d, J = 8.3 Hz, 2H), formate 7.60 (d, J = 8.3 Hz, 2H), 7.44-7.41 (m,2H), 7.38-7.24 (m, 10H), 7.05-6.99 (m, 3H), 6.93 (dd, J = 2.1, 8.2 Hz,1H), 6.66 (d, J = 9.8 Hz, 1H), 5.41 (dd, J = 5.7, 7.7 Hz, 1H), 5.25-5.18(m, 1H), 4.31 (s, 2H), 4.08 (t, J = 6.0 Hz, 2H), 3.85 (dd, J = 6.8, 9.7Hz, 2H), 3.77 (s, 2H), 3.59 (t, J = 6.8 Hz, 2H), 3.35-3.30 (m, 2H),3.23-3.19 (m, 2H), 2.15-2.07 (m, 2H).

Example 27.1-Benzylpiperidin-4-yl(S)-2-hydroxy-2-(3-((4-((3-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)phenyl)ureido)-methyl)benzyl)oxy)phenyl)-2-phenylacetate(Compound 166)

To a suspension of(R)-4-(((tert-butoxycarbonyl)(2-((tert-butyldimethylsilyl)oxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzoicacid (0.337 g, 0.59 mmol) in toluene (5 mL) was added triethylamine(0.108 mL, 0.77 mmol) and diphenyl phosphoraylazide (0.153 mL, 0.71mmol). The reaction mixture was heated at 90° C. for 3.5 hours. Asolution of 1-benzylpiperidin-4-yl(S)-2-(3-((4-(aminomethyl)-benzyl)oxy)phenyl)-2-hydroxy-2-phenylacetatedihydrochloride (0.37 g, 0.59 mmol) and triethylamine (0.165 mL, 1.19mmol) in DMF (2 mL) was added and the reaction mixture heated at 90° C.for 18 hours. The reaction mixture was diluted with ethyl acetate andwashed with saturated aqueous sodium hydrogen carbonate and brine. Theorganic phase was dried over anhydrous magnesium sulfate, filtered andthe filtrate evaporated at reduced pressure. The residue was dissolvedin MeCN (1 mL) and a solution of HCl-dioxan (4 mL) added. The reactionmixture was stirred at room temperature for 1 hour. The solvent wasevaporated at reduced pressure and the residue purified by reversepreparative HPLC.

The following compounds were prepared by this method:

N Structure 167

168

Rt Salt N (min) Method NMR data (400 MHz) (2 eq unless stated) 166 2.6011 (MeOD); δ 8.57 (s, 1H), 8.26 (d, J = 9.8 Hz, 1H), 7.47 (d, J = 8.5Hz, 2H), TFA 7.39-7.32 (m, 16H), 7.29-7.23 (m, 2H), 7.04-6.94 (m, 4H),6.65 (d, J = 9.8 Hz, 1H), 5.34 (dd, J = 4.3, 9.0 Hz, 1H), 5.05 (s, 2H),4.42 (s, 2H), 4.11 (s, 2H), 4.10-4.03 (m, 2H), 3.64 (s, 2H), 3.16-3.06(m, 2H), 2.95 (d, J = 11.8 Hz, 2H), 2.17 (dd, J = 9.9, 12.2 Hz, 2H),1.71-1.65 (m, 1H), 1.57 (d, J = 13.2 Hz, 2H), 1.33-1.18 (m, 2H). 1672.57 11 (MeOD); δ 8.57 (s, 1H), 8.22 (d, J = 9.9 Hz, 1H), 7.40-7.18 (m,18H), mono-formate 7.03-6.95 (m, 4H), 6.86 (dd, J = 1.9, 8.1 Hz, 1H),6.64 (d, J = 9.9 Hz, 1H), 5.32 (dd, J = 5.0, 8.4 Hz, 1H), 5.05 (s, 2H),4.43 (s, 2H), 4.09 (s, 2H), 4.06 (dd, J = 3.5, 6.5 Hz, 2H), 3.85 (s,3H), 3.53 (s, 2H), 3.09-3.05 (m, 2H), 2.91-2.86 (m, 2H), 2.08-1.99 (m,2H), 1.65-1.62 (m, 1H), 1.54 (d, J = 13.2 Hz, 2H), 1.32-1.19 (m, 2H).168 2.58 11 (MeOD); δ 8.57 (s, 1H), 8.25 (d, J = 9.9 Hz, 1H), 8.08 (d, J= 8.3 Hz, 1H), mono-formate 7.37-7.24 (m, 18H), 7.08-6.94 (m, 4H), 6.64(d, J = 9.9 Hz, 1H), 5.32 (dd, J = 4.4, 8.7 Hz, 1H), 5.05 (s, 2H), 4.93(d, J = 2.1 Hz, 1H), 4.42 (s, 2H), 4.09-4.04 (m, 4H), 3.91 (s, 3H), 3.60(s, 2H), 3.11-3.05 (m, 2H), 2.95-2.88 (m, 2H), 2.11 (t, J = 11.4 Hz,1H), 1.71-1.60 (m, 1H), 1.59-1.53 (m, 2H), 1.24 (ddd, J = 6.3, 12.3,18.3 Hz, 2H).

Biological Characterization. Example 28. M3 Receptor Radioligand BindingAssay

Human M3 receptor membranes (15 ug/well) from Perkin Elmer wereincubated with 0.52 nM Scopolamine Methyl Chloride, (N-methyl-3H) withor without test compounds, or a saturating concentration of Atropine (5μM) for the determination of non-specific binding. The assay was carriedout in 96-well polypropylene plates in a volume of 250 ul. The assaybuffer used was 50 mM Tris-HCl, 154 mM NaCl (pH 7.4). The final assayconcentration of DMSO was 0.5% (v/v). The plates were sealed andincubated for 2 h at room temperature on an orbital shaker (slow speed).Membranes were harvested onto 96-well unifilter GF/C filter platespre-treated with 0.5% polyethyleneimine (v/v), using a filter manifold,washed four times with 200 ul of assay buffer. The plates were driedbefore addition of 50 μl of microscint-0, sealed then read in a TriluxMicrobeta scintillation counter. IC50 values are determined fromcompetition curves using a non-linear curve fitting program. Ki valueswere calculated from 1050 values by the Cheng and Prusoff equation.

The M3 Ki values of the compounds according to the invention are lessthan 50 nM, most of them even less than 10 nM. The preferred compoundsaccording to the invention have Ki value less than 4 nM or even lessthan 3 nM for the enantiomeric mixture and at least for one of theenantiomeric pure form (S or R) on the stereogenic center (2).

Example 29. β2 Adrenoceptor Radioligand Binding Assay

Human β₂ adrenoceptor membranes (7.5 ug/well) from Perkin Elmer wereincubated with 0.3 nM 125-I Cyanopindolol with or without testcompounds, or a saturating concentration of s-propranolol (2 μM) for thedetermination of non-specific binding. The assay was carried out in96-well polypropylene plates in a volume of 200 ul. The assay bufferused was 25 mM HEPES, 0.5% BSA (w/v), 1 mM EDTA, 0.02% ascorbic acid(v/v), (pH 7.4). The final assay concentration of DMSO was 0.5% (v/v).The plates were sealed and incubated for 1 h at room temperature on anorbital shaker (slow speed). Membranes were harvested onto 96-wellunifilter GF/C filter plates pre-treated with 0.5% polyethyleneimine(v/v), using a filter manifold, washed six times with 200 ul of washbuffer containing 10 mM HEPES and 500 mM NaCl. The plates were driedbefore addition of 50 μl of microscint-0, sealed then read in a TriluxMicrobeta scintillation counter. 1050 values are determined fromcompetition curves using a non-linear curve fitting program. Ki valueswere calculated from 1050 values by the Cheng and Prusoff equation.

The β2 Ki values of the compounds according to the invention are lessthan 50 nM, most of them even less than 10 nM.

In the following table the compounds tested are classified in terms ofbinding affinity according to the following ranges:

No M3 B2 No M3 B2 No M3 B2 No M3 B2 No M3 B2  1 ++ +++ 32J ++ +++  62+++ +++ 104 +++ ++ 146 ++ +  2 ++ ++ 32K ++ +++  63 +++ +++ 105 ++ ++147 ++ +++  3 ++ +++ 32L ++ +  64 +++ ++ 106 ++ ++ 148 ++ +++  4 ++ +++32M ++ +  65 +++ ++ 107 ++ +++ 149 +++ ++  5 ++ ++ 33 +++ +++  66 ++ +++108 ++ ++ 150 +++ +++  6 + +++ 33A ++ +++  67 +++ +++ 109 ++ ++ 151 ++++++  7 + ++ 34 + ++  68 ++ ++ 110 ++ ++ 152 +++ ++  8 + ++ 35 +++ +++ 69 ++ ++ 111 ++ ++ 153 +++ +++  9 ++ +++ 36 +++ +++  70 ++ ++ 112 +++++ 154 +++ +++ 10 ++ ++ 36A ++ ++  71 ++ + 113 ++ ++ 155 ++ +++ 11 ++++++ 37 +++ +++  72 ++ + 114 ++ ++ 156 +++ +++ 12 + + 38 +++ +++  73 +++++ 115 ++ ++ 157 ++ + 12A ++ +++ 39 ++ +++  74 ++ ++ 116 ++ +++ 158 +++++ 13 +++ +++ 40 ++ ++  75 ++ + 117 ++ +++ 159 ++ +++ 14 + +++ 41 ++ ++ 76 ++ ++ 118 +++ ++ 160 ++ +++ 15 +++ +++ 42 +++ +++  77 ++ ++ 119 +++++ 161 ++ +++ 16 + ++ 42A +++ ++  78 +++ +++ 120 +++ +++ 162 ++ +++ 17 +++ 42B +++ +++  79 +++ +++ 121 +++ +++ 163 ++ +++ 18 + +++ 42B ++ +++ 80 ++ +++ 122 ++ + 164 ++ ++ 19 ++ +++ 42C ++ +++  81 ++ ++ 123 ++ ++165 ++ +++ 20 + +++ 42D ++ +++  82 ++ ++ 124 ++ ++ 166 ++ ++ 21 ++ +++42E ++ +++  83 + ++ 125 ++ ++ 167 ++ ++ 22 + +++ 42F ++ +++  84 + ++ 126++ ++ 168 ++ ++ 23 ++ ++ 43 +++ +++  85 ++ +++ 127 +++ +++ 24 + +++ 44++ +++  86 ++ +++ 128 ++ +++ 25 ++ +++ 45 ++ ++  87 ++ ++ 129 ++ +++ 26++ +++ 46 ++ +++  88 +++ ++ 130 ++ ++ 27 + ++ 47 ++ +++  89 ++ +++ 131++ +++ 28 ++ ++ 48 + +++  90 ++ ++ 132 ++ +++ 29 + +++ 49 ++ +++  91 +++++ 133 +++ +++ 30 ++ ++ 50 ++ +  92 +++ +++ 134 ++ +++ 31 +++ +++ 51 +++++  93 ++ +++ 135 ++ +++ 32 ++ +++ 52 ++ +++  94 +++ +++ 136 ++ +++ 32A++ +++ 53 + +  95 +++ +++ 137 ++ +++ 32B +++ +++ 54 ++ +++  96 +++ +++138 ++ ++ 32C ++ +++ 55 ++ +  97 ++ +++ 139 ++ +++ 32D ++ +++ 56 + +  98++ ++ 140 ++ ++ 32E ++ ++ 57 ++ ++  99 ++ ++ 141 ++ ++ 32F ++ +++ 58 ++++ 100 +++ ++ 142 ++ +++ 32G ++ ++ 59 ++ ++ 101 +++ +++ 143 ++ ++ 32H +++++ 60 ++ ++ 102 +++ +++ 144 ++ +++ 32I +++ +++ 61 ++ +++ 103 +++ ++ 145++ ++ +++: IC50 < 0.3 nM ++: IC50 in the range 0.3 to 3 nM +: IC50 > 3nM

Where a numerical limit or range is stated herein, the endpoints areincluded. Also, all values and subranges within a numerical limit orrange are specifically included as if explicitly written out.

As used herein the words “a” and “an” and the like carry the meaning of“one or more.”

Obviously, numerous modifications and variations of the presentinvention are possible in light of the above teachings. It is thereforeto be understood that, within the scope of the appended claims, theinvention may be practiced otherwise than as specifically describedherein.

All patents and other references mentioned above are incorporated infull herein by this reference, the same as if set forth at length.

1.-17. (canceled)
 18. A method for the prevention and/or treatment of abroncho-obstructive or inflammatory disease, comprising administering toa subject in need thereof an effective amount of a compound of formula I

wherein: Q is a group of formula

Y is Y2 or Y1 which are divalent groups of formula

wherein A1 and A2 are independently absent or selected from the groupconsisting of (C₁-C₁₂)alkylene, (C₃-C₈)cycloalkylene, and(C₃-C₈)heterocycloalkylene, each of which are optionally substituted byone or more substituents selected from the group consisting of(C₁-C₆)alkyl, aryl(C₁-C₆)alkyl, and heteroaryl(C₁-C₆)alkyl; B is absentor is selected from the group consisting of (C₃-C₈)cycloalkylene,(C₃-C₈)heterocycloalkylene, arylene, and heteroarylene, each of which isoptionally substituted by one or more groups selected from the groupconsisting of —OH, halogen, —CN, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,(C₁-C₆)haloalkyl, (C₁-C₆)haloalkoxy, and aryl(C₁-C₆)alkyl; C is absentor is selected from the group consisting of —O—, —C(O)—, —OC(O)—,—(O)CO—, —S—, —S(O)—, —S(O)₂—, and —N(R₇)—, or is one of the followinggroups C1-C23

wherein R₇ is in each occurrence independently H or selected from thegroup consisting of linear or branched (C₁-C₈)alkyl, aryl(C₁-C₆)alkyl,arylsulfanyl, arylsulfinyl, arylsulfonyl, (C₃-C₈)cycloalkyl,(C₃-C₈)heterocycloalkyl, aryl, and heteroaryl; D is absent or isselected from the group consisting of (C₁-C₁₂)alkylene,(C₂-C₁₂)alkenylene, (C₂-C₆)alkynylene, arylene, heteroarylene,(C₃-C₈)cycloalkylene, (C₃-C₈)heterocycloalkylene; wherein said arylene,heteroarylene, (C₃-C₈)cycloalkylene, and (C₃-C₈)heterocycloalkylene isoptionally substituted by one or more groups selected from the groupconsisting of —OH, halogen, —CN, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,(C₁-C₆)haloalkyl, (C₁-C₆)haloalkoxy, and aryl(C₁-C₆)alkyl; n is at eachoccurrence independently 0 or an integer from 1 to 3; m is at eachoccurrence independently an integer from 1 to 3; E is absent or isselected from the group consisting of —O—, —NR₇—, —NR₇—C(O)—,—C(O)—NR₇—, —OC(O)—, —C(O)—(CH₂)_(n)—O—; —NR₇—C(O)—(CH₂)_(n)—O—,—NR₇—C(O)—NR₇—, and —S—; G is arylene or heteroarylene, each of which isoptionally substituted by one or more substituents selected from thegroup consisting of halogen, —OH, oxo (═O), —SH, —NO₂, —CN, —CON(R₆)₂,—NH₂, —NHCOR₆, —CO₂R₆, (C₁-C₁₀)alkylsulfanyl, (C₁-C₁₀)alkylsulfinyl,(C₁-C₁₀)alkylsulfonyl, (C₁-C₁₀)alkyl, aryl, haloaryl, heteroaryl, and(C₁-C₁₀)alkoxy; R₁ is selected from the group consisting of(C₃-C₈)cycloalkyl, (C₃-C₈)heterocycloalkyl, aryl, heteroaryl,aryl(C₁-C₆)alkyl, heteroaryl(C₁-C₆)alkyl, and(C₃-C₈)cycloalkyl(C₁-C₆)alkyl, each of which is optionally substitutedby one or more groups selected independently from the group consistingof halogen, (C₁-C₈)alkyl, and (C₁-C₁₀)alkoxy; s is 0 or an integer from1 to 3; R₂ is a nitrogen containing group which is: a group (a) which is—NR₃R₄ wherein R₃ and R₄ are independently hydrogen or (C₁-C₄) alkyl; ora group (b) of formula J1, J2, J3, J4 or J5

R₅ is a group of formula K

wherein p is 0 or an integer from 1 to 4; q is 0 or an integer from 1 to4; P is absent or is a divalent moiety selected from the groupconsisting of O, S, SO, SO₂, CO, NR₆ CH═CH, N(R₆)SO₂, N(R₆)COO,N(R₆)C(O), SO₂N(R₆), OC(O)N(R₆), and C(O)N(R₆); W is H or is selectedfrom the group consisting of (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, aryl, andheteroaryl, each of which is optionally substituted by one or moresubstituents selected independently from the group consisting ofhalogen, —OH, oxo (═O), —SH, —NO₂, —CN, —CON(R₆)₂, —NH₂, —NHCOR₆,—CO₂R₆, (C₁-C₁₀)alkylsulfanyl, (C₁-C₁₀)alkylsulfinyl,(C₁-C₁₀)alkylsulfonyl, (C₁-C₁₀)alkyl, and (C₁-C₁₀)alkoxy; R₆ is at eachoccurrence independently H or selected from the group consisting of(C₁-C₁₀)alkyl, (C₁-C₆)haloalkyl, (C₂-C₆)alkynyl, (C₂-C₆)alkenyl,(C₃-C₈)cycloalkyl, heteroaryl, and aryl, each of which is optionallysubstituted by one or more substituents selected from the groupconsisting of halogen, —OH, oxo (═O), —SH, —NO₂, —CN, —CONH₂, —COOH,(C₁-C₁₀)alkoxycarbonyl, (C₁-C₁₀)alkylsulfanyl, (C₁-C₁₀)alkylsulfinyl,(C₁-C₁₀)alkylsulfonyl, (C₁-C₁₀)alkyl, and (C₁-C₁₀)alkoxy; or apharmaceutically acceptable salt thereof.
 19. A method according toclaim 18, wherein R₂ is a group of formula J3:

and R₅ is a group of formula K, wherein p is 0 or 1, P is absent or isCO, q is absent or is 1, and W is H, (C₁-C₆)alkyl, or aryl.
 20. A methodaccording to claim 19, wherein R₅ is methyl or benzyl.
 21. A methodaccording to claim 18, wherein G is arylene and R₁ is aryl, optionallysubstituted by one or more group independently selected from the groupconsisting of halogen, (C₁-C₈)alkyl, and (C₁-C₁₀)alkoxy.
 22. A methodaccording to claim 21, wherein A1 and A2 are independently absent orselected from the group consisting of methylene, ethylene, propylene,butylene, pentylene, hexylene, heptylene, octylene, and nonylene, G isphenylene, and R₁ is phenyl, optionally substituted by one or more groupindependently selected from the group consisting of halogen,(C₁-C₈)alkyl, and (C₁-C₁₀)alkoxy.
 23. A method according to claim 18,wherein E is —O—, —C(O)—(CH₂)_(n)—O—, or —NR₇—C(O)—(CH₂)_(n)—O—; G isphenylene, wherein E is linked to the phenyl ring G in the metaposition, and R₁ is phenyl, optionally substituted by one or more groupsselected from the group consisting of halogen, (C₁-C₈)alkyl, and(C₁-C₁₀)alkoxy.
 24. A method according to claim 18, wherein R₂ is J1,J2, or J5


25. A method according to claim 19, wherein the absolute configurationof carbon (1) is that shown hereinbelow:


26. A method according to claim 18, wherein Y is a divalent group offormula Y2:

A2 is absent and A1 is independently selected from the group consistingof methylene, ethylene, n-propylene, isopropylene, butylene, pentylene,hexylene, and octylene; B is absent or is selected from the groupconsisting of piperidinylene, phenylene, pyridine-diyl, andpyrazole-diyl; wherein B is optionally substituted by one or more groupsselected from the group consisting of —OH, fluorine, chlorine, bromine,—CN, methyl, methoxy, ethoxy, isopropoxy, trifluoromethyl, andtrifluoromethoxy; C is absent or is —O— or —C(O)—, or is one of thegroups C1, C2, C4, C7, C8, C9, C10, C12, C13, C14, C15, C16, C17, C18,C19, C20, C21 C22 C23, wherein R₇ is in each occurrence independently H,methyl, ethyl, or benzyl; D is absent or is para-phenylene,meta-phenylene, cyclohexanediyl, piperidindiyl, pyrrolidindiyl orazetidindiyl; n is at each occurrence independently 0 or an integer from1 to 3; m is at each occurrence independently an integer from 1 to 3; Eis absent or is —O—, —NH—, —NH—C(O)—, —C(O)—NH—, —C(O)—CH₂—O—, or—NH—C(O)—CH₂—O—; G is meta-phenylene or para-phenylene; R₁ isthiophenyl, cyclohexyl, cyclopentyl, or phenyl, each of which isoptionally substituted by one or more groups selected independently fromthe group consisting of fluorine, methyl, ethyl, and methoxy; s is 0, 1,or 2 R₂ is: a group (a) which is —NR₃R₄ wherein R₃ and R₄ are methyl; ora group (b) of formula J1, J2, J3, J4 or J5 wherein R₅ is methyl orbenzyl.
 27. A method according to claim 18, comprising administering awhich is selected from the group consisting of:(1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-((5-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)pentyl)oxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-((5-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)pentyl)oxy)phenyl)-2-(p-tolyl)acetate;(1-benzylpiperidin-4-yl)methyl2-(4-fluorophenyl)-2-hydroxy-2-(3-((5-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)pentyl)oxy)phenyl)-acetate;(1-benzylpiperidin-4-yl)methyl2-(3-fluorophenyl)-2-hydroxy-2-(3-((5-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)pentyl)oxy)phenyl)-acetate;(1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-((5-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)pentyl)oxy)phenyl)-2-(m-tolyl)acetate;(1-benzylpiperidin-4-yl)methyl2-(2-chlorophenyl)-2-hydroxy-2-(3-((5-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)pentyl)oxy)-phenyl)acetate;(1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-((5-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)pentyl)oxy)phenyl)-2-(o-tolyl)acetate;(1-benzylpiperidin-4-yl)methyl2-(2-ethylphenyl)-2-hydroxy-2-(3-((5-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)pentyl)oxy)phenyl)-acetate;(1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-((5-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)pentyl)oxy)phenyl)-2-(thiophen-2-yl)acetate;(1-benzylpiperidin-4-yl)methyl2-cyclohexyl-2-hydroxy-2-(3-((5-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)pentyl)oxy)phenyl)-acetate;(1-benzylpiperidin-4-yl)methyl2-(3-ethylphenyl)-2-hydroxy-2-(3-((5-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)pentyl)oxy)phenyl)-acetate;(R)-quinuclidin-3-yl2-hydroxy-2-(3-((5-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)pentyl)oxy)phenyl)-2-(4-methoxyphenyl)acetate;(R)-quinuclidin-3-yl2-cyclopentyl-2-hydroxy-2-(3-((5-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)pentyl)oxy)phenyl)acetate;(S)-(1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-((5-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)pentyl)oxy)phenyl)-2-phenylacetate;(R)-(1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-((5-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)pentyl)oxy)phenyl)-2-phenylacetate;(R)-quinuclidin-3-yl2-hydroxy-2-(3-((5-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)pentyl)oxy)phenyl)-2-phenylacetate;(R)—(R)-quinuclidin-3-yl2-hydroxy-2-(3-((5-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)pentyl)oxy)phenyl)-2-phenylacetate;(S)-2-(dimethylamino)ethyl2-hydroxy-2-(3-((5-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)pentyl)oxy)phenyl)-2-phenylacetate;(R)-2-(dimethylamino)ethyl2-hydroxy-2-(3-((5-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)pentyl)oxy)phenyl)-2-phenylacetate;(S)—(R)-1-methylpyrrolidin-3-yl2-hydroxy-2-(3-((5-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)pentyl)oxy)phenyl)-2-phenylacetate;(R)—(R)-1-methylpyrrolidin-3-yl2-hydroxy-2-(3-((5-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)pentyl)oxy)phenyl)-2-phenylacetate;(S)-1-methylpiperidin-4-yl2-hydroxy-2-(3-((5-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)pentyl)oxy)phenyl)-2-phenylacetate;(R)-1-methylpiperidin-4-yl2-hydroxy-2-(3-((5-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)pentyl)oxy)phenyl)-2-phenylacetate;(S)-(1-methylpiperidin-4-yl)methyl2-hydroxy-2-(3-((5-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)pentyl)oxy)phenyl)-2-phenylacetate;(R)-(1-methylpiperidin-4-yl)methyl2-hydroxy-2-(3-((5-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)pentyl)oxy)phenyl)-2-phenylacetate;(S)—(R)-1-methylpiperidin-3-yl2-hydroxy-2-(3-((5-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)pentyl)oxy)phenyl)-2-phenylacetate;(S)-1-methylazetidin-3-yl2-hydroxy-2-(3-((5-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)pentyl)oxy)phenyl)-2-phenylacetate;(R)-(1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-((6-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)hexyl)oxy)phenyl)-2-phenylacetate;(S)-(1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-((7-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)heptyl)oxy)phenyl)-2-phenylacetate;(S)-(1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-((6-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)hexyl)oxy)phenyl)-2-phenylacetate;(S)-(1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-((8-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)octyl)oxy)phenyl)-2-phenylacetate;(S)-(1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-((1-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzoyl)piperidin-4-yl)methoxy)phenyl)-2-phenylacetate;(S)-(1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-(3-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzamido)propoxy)-phenyl)-2-phenylacetate;(S)-(1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-((4-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-piperidine-1-carbonyl)benzyl)oxy)phenyl)-2-phenylacetate;(R)-(1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-(2-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzamido)ethoxy-phenyl)-2-phenylacetate;(S)-(1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-((3-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-piperidine-1-carbonyl)benzyl)oxy)phenyl)-2-phenylacetate;(S)-(1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-(2-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)piperidin-1-yl)-2-oxoethoxy)phenyl)-2-phenylacetate;(S)-(1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-(3-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzamido)propoxy)-phenyl)-2-phenylacetate;(S)-(1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-(2-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzamido)ethoxy)-phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-(2-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzamido)ethyl)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-(2-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzamido)ethyl)phenyl)-2-phenylacetate;(S)-(1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-((1-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-benzoyl)azetidin-3-yl)methoxy)phenyl)-2-phenylacetate;(S)-(1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-((1-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzoyl)azetidin-3-yl)methoxy)phenyl)-2-phenylacetate;(S)-(1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-((4-((3-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)propyl)carbamoyl)benzyl)-oxy)phenyl)-2-phenylacetate;(R)-(1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-((4-((3-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)propyl)carbamoyl)benzyl)-oxy)phenyl)-2-phenylacetate;(S)-(1-benzylpiperidin-4-yl)methyl2-(3-((3-(benzyl(3-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)propyl)carbamoyl)benzyl)oxy)-phenyl)-2-hydroxy-2-phenylacetate;(R)-quinuclidin-3-yl2-hydroxy-2-(3-(4-((5-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)pentyl)oxy)benzamido)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-((4-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)butyl)carbamoyl)phenyl)-2-phenylacetate;(R)-quinuclidin-3-yl2-hydroxy-2-(3-((4-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)butyl)carbamoyl)phenyl)-2-phenylacetate;(R)-1-methylpyrrolidin-3-yl2-hydroxy-2-(3-((4-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)butyl)carbamoyl)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-((3-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzamido)propyl)-carbamoyl)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(4-((5-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)pentyl)oxy)phenyl)-2-phenylacetate;(R)-quinuclidin-3-yl2-hydroxy-2-(4-((5-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)pentyl)oxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(4-((4-((4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzamido)methyl)-benzyl)oxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-((((5-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)pentyl)oxy)carbonyl)amino)-phenyl)-2-phenylacetate;(R)-quinuclidin-3-yl2-hydroxy-2-(3-(5-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)pentanamido)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-(3-(3-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzamido)propyl)-ureido)phenyl)-2-phenylacetate;(S)-(1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-(3-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-3-methoxybenzamido)-propoxy)phenyl)-2-phenylacetate;(S)-(1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-(3-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-2-methoxybenzamido)-propoxy)phenyl)-2-phenylacetate;(S)-(1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-(3-(6-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)nicotinamido)-propoxy)phenyl)-2-phenylacetate;(S)-(1-benzylpiperidin-4-yl)methyl2-(3-(3-(3-ethoxy-4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzamido)-propoxy)phenyl)-2-hydroxy-2-phenylacetate;(S)-(1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-(3-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-3-(trifluoromethoxy)-benzamido)propoxy)phenyl)-2-phenylacetate;(S)-(1-benzylpiperidin-4-yl)methyl2-(3-(3-(2-fluoro-4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-3-methoxybenzamido)-propoxy)phenyl)-2-hydroxy-2-phenylacetate;(S)-(1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-(3-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-3-isopropoxybenzamido)-propoxy)phenyl)-2-phenylacetate;(S)-(1-benzylpiperidin-4-yl)methyl2-(3-(3-(2-chloro-4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzamido)propoxy)-phenyl)-2-hydroxy-2-phenylacetate;(S)-(1-benzylpiperidin-4-yl)methyl2-(3-(3-(2-fluoro-4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-5-methoxybenzamido)-propoxy)phenyl)-2-hydroxy-2-phenylacetate;(S)-(1-benzylpiperidin-4-yl)methyl2-(3-(3-(2-chloro-4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-5-methoxybenzamido)-propoxy)phenyl)-2-hydroxy-2-phenylacetate;(S)-(1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-(3-(5-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)picolinamido)-propoxy)phenyl)-2-phenylacetate;(S)-(1-benzylpiperidin-4-yl)methyl2-(3-(3-(2,3-difluoro-4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzamido)propoxy)-phenyl)-2-hydroxy-2-phenylacetate;(S)-(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(3-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-3-(trifluoromethyl)-benzamido)propoxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-((4-(4-(2-(((R)-2-hydroxy-2-(4-hydroxy-6-oxo-5,6-dihydronaphthalen-1-yl)ethyl)amino)ethyl)piperidine-1-carbonyl)-benzyl)oxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)piperidin-1-yl)-2-oxoethoxy)phenyl)-2-phenylacetate;(S)-(1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-(2-((4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-3-methoxyphenyl)amino)-2-oxoethoxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-(3-(2-((2-fluoro-4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-5-methoxyphenyl)amino)-2-oxoethoxy)phenyl)-2-hydroxy-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-((4-((4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzamido)methyl)-benzyl)oxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-((4-((4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzamido)methyl)-benzyl)oxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-((4-((4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-2-methoxybenzamido)-methyl)benzyl)oxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-((4-((4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-3-methoxybenzamido)-methyl)benzyl)oxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-((2-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzamido)ethyl)-amino)-2-oxoethoxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(4-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzoyl)piperazin-1-yl)-2-oxoethoxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(4-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzamido)piperidin-1-yl)-2-oxoethoxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-((2-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzamido)ethyl)-(methyl)amino)-2-oxoethoxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(4-((4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzamido)-methyl)piperidin-1-yl)-2-oxoethoxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(((1R,4S)-4-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzamido)-cyclohexyl)amino)-2-oxoethoxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(((1R,3S)-3-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzamido)-cyclobutyl)amino)-2-oxoethoxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(9-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzoyl)-3,9-diazaspiro[5.5]undecan-3-yl)-2-oxoethoxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-((1-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzoyl)piperidin-4-yl)amino)-2-oxoethoxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-((1-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzoyl)azetidin-3-yl)amino)-2-oxoethoxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(3-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzamido)azetidin-1-yl)-2-oxoethoxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(((R)-1-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzoyl)-pyrrolidin-3-yl)amino)-2-oxoethoxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(((S)-1-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzoyl)-piperidin-3-yl)amino)-2-oxoethoxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(((S)-1-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-benzoyl)pyrrolidin-3-yl)amino)-2-oxoethoxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(((R)-1-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzoyl)-piperidin-3-yl)amino)-2-oxoethoxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-((S)-3-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzamido)piperidin-1-yl)-2-oxoethoxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-((S)-3-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzamido)pyrrolidin-1-yl)-2-oxoethoxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl (S)-2-hydroxy-2-(3-(2-((3aR,6aR)-5-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzoyl)-hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)-2-oxoethoxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-((R)-3-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzamido)-piperidin-1-yl)-2-oxoethoxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-((R)-3-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzamido)-pyrrolidin-1-yl)-2-oxoethoxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-((3aS,6aS)-5-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzoyl)-hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)-2-oxoethoxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-((1-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-3-methoxybenzoyl)azetidin-3-yl)amino)-2-oxoethoxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(9-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-3-methoxybenzoyl)-3,9-diazaspiro[5.5]undecan-3-yl)-2-oxoethoxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(4-((4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-3-methoxybenzamido)methyl)piperidin-1-yl)-2-oxoethoxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(9-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-2-methoxybenzoyl)-3,9-diazaspiro[5.5]undecan-3-yl)-2-oxoethoxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-((1-(4-(MR)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-2-methoxybenzoyl)azetidin-3-yl)amino)-2-oxoethoxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-(3-(2-(ethyl(2-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzamido)ethyl)amino)-2-oxoethoxy)phenyl)-2-hydroxy-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-((2-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzamido)ethyl)-(methyl)amino)-2-oxoethoxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-((3-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzamido)propyl)-amino)-2-oxoethoxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(4-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzoyl)piperazin-1-yl)-2-oxoethoxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-(3-(2-(benzyl(2-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzamido)ethyl)amino)-2-oxoethoxy)phenyl)-2-hydroxy-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(((1R,3S)-3-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzamido)-cyclobutyl)amino)-2-oxoethoxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(4-((4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzamido)-methyl)piperidin-1-yl)-2-oxoethoxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(((1R,4S)-4-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzamido)-cyclohexyl)amino)-2-oxoethoxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-((1-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzoyl)piperidin-4-yl)amino)-2-oxoethoxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(4-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzamido)piperidin-1-yl)-2-oxoethoxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(6-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzoyl)-2,6-diazaspiro[3.3]heptan-2-yl)-2-oxoethoxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(7-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzoyl)-2,7-diazaspiro[3.5]nonan-2-yl)-2-oxoethoxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(9-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzoyl)-3,9-diazaspiro[5.5]undecan-3-yl)-2-oxoethoxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(2-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzoyl)-2,7-diazaspiro[3.5]nonan-7-yl)-2-oxoethoxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(((1-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzoyl)piperidin-4-yl)methyl)amino)-2-oxoethoxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(6-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzoyl)-2,6-diazaspiro[3.5]nonan-2-yl)-2-oxoethoxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(9-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzoyl)-2,9-diazaspiro[5.5]undecan-2-yl)-2-oxoethoxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(9-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzoyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)-2-oxoethoxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-((1-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzoyl)azetidin-3-yl)amino)-2-oxoethoxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(3-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzamido)azetidin-1-yl)-2-oxoethoxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-((2-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzamido)ethyl)-amino)-2-oxoethoxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(((R)-1-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzoyl)-pyrrolidin-3-yl)amino)-2-oxoethoxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(((R)-1-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzoyl)-piperidin-3-yl)amino)-2-oxoethoxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(((S)-1-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzoyl)-piperidin-3-yl)amino)-2-oxoethoxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(((S)-1-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzoyl)-pyrrolidin-3-yl)amino)-2-oxoethoxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-((S)-3-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzamido)-piperidin-1-yl)-2-oxoethoxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-((S)-3-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzamido)-pyrrolidin-1-yl)-2-oxoethoxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-((R)-3-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzamido)-pyrrolidin-1-yl)-2-oxoethoxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-((3aR,6aR)-1-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzoyl)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)-2-oxoethoxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-((3aS,6aS)-1-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzoyl)-hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)-2-oxoethoxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-((R)-3-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzamido)-piperidin-1-yl)-2-oxoethoxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-((4-(((1R,3S)-3-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzamido)-cyclobutyl)carbamoyl)benzyl)oxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-((4-(9-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzoyl)-3,9-diazaspiro[5.5]undecane-3-carbonyl)benzyl)oxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-((4-(6-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzoyl)-2,6-diazaspiro[3.3]heptane-2-carbonyl)benzyl)oxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-((4-(7-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzoyl)-2,7-diazaspiro[3.5]nonane-2-carbonyl)benzyl)oxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-((4-(4-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzoyl)piperazine-1-carbonyl)benzyl)oxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-((4-(2-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzoyl)-2,7-diazaspiro[3.5]nonane-7-carbonyl)benzyl)oxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-((4-(6-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzoyl)-2,6-diazaspiro[3.5]nonane-2-carbonyl)benzyl)oxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-((4-(9-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzoyl)-1-oxa-4,9-diazaspiro[5.5]undecane-4-carbonyl)benzyl)oxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-((4-(9-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzoyl)-2,9-diazaspiro[5.5]undecane-2-carbonyl)benzyl)oxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-((4-(((1R,3S)-3-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzamido)-cyclobutyl)carbamoyl)benzyl)oxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-((4-(((1R,3S)-3-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-3-methoxybenzamido)cyclobutyl)carbamoyl)benzyl)oxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-((4-((2-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzamido)ethyl)-carbamoyl)benzyl)oxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-((4-((2-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-3-methoxybenzamido)-ethyl)carbamoyl)benzyl)oxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(((1R,3S)-3-(3-hydroxy-4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-benzamido)cyclobutyl)amino)-2-oxoethoxy)phenyl)-2-phenylacetate;(S)-(1-benzylpiperidin-4-yl)methyl2-(3-(2-(((1R,3S)-3-(2-fluoro-4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzamido)-cyclobutyl)amino)-2-oxoethoxy)phenyl)-2-hydroxy-2-phenylacetate;(S)-(1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-(2-(((1R,3S)-3-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-3-methylbenzamido)cyclobutyl)amino)-2-oxoethoxy)phenyl)-2-phenylacetate;(S)-(1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-(2-(((1R,3S)-3-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-2-methoxybenzamido)cyclobutyl)amino)-2-oxoethoxy)phenyl)-2-phenylacetate;(S)-(1-benzylpiperidin-4-yl)methyl2-hydroxy-2-(3-(2-(((1R,3S)-3-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-3-methoxybenzamido)cyclobutyl)amino)-2-oxoethoxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-(3-(2-(((1R,3S)-3-(3-fluoro-4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzamido)-cyclobutyl)amino)-2-oxoethoxy)phenyl)-2-hydroxy-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-(3-(2-(((1R,3S)-3-(2-chloro-4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzamido)-cyclobutyl)amino)-2-oxoethoxy)phenyl)-2-hydroxy-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-(3-(2-(((1R,3S)-3-(2,3-difluoro-4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzamido)-cyclobutyl)amino)-2-oxoethoxy)phenyl)-2-hydroxy-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-(3-(2-(((1R,3S)-3-(3-chloro-4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzamido)-cyclobutyl)amino)-2-oxoethoxy)phenyl)-2-hydroxy-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-(3-(2-(((1R,3S)-3-(2-bromo-4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzamido)-cyclobutyl)amino)-2-oxoethoxy)phenyl)-2-hydroxy-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-(3-(2-(((1R,3S)-3-(2-chloro-4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-5-methoxybenzamido)cyclobutyl)amino)-2-oxoethoxy)phenyl)-2-hydroxy-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(((1R,3S)-3-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-3-(trifluoromethyl)benzamido)cyclobutyl)amino)-2-oxoethoxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-(3-(2-(((1R,3S)-3-(2-fluoro-4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-3-methoxybenzamido)cyclobutyl)amino)-2-oxoethoxy)phenyl)-2-hydroxy-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-(3-(2-(((1R,3S)-3-(3-ethoxy-4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzamido)-cyclobutyl)amino)-2-oxoethoxy)phenyl)-2-hydroxy-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(((1R,3S)-3-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-3-(trifluoromethoxy)benzamido)cyclobutyl)amino)-2-oxoethoxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-(3-(2-(((1R,3S)-3-(2-fluoro-4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-5-methoxybenzamido)cyclobutyl)amino)-2-oxoethoxy)phenyl)-2-hydroxy-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(((1R,3S)-3-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-3-isopropoxybenzamido)cyclobutyl)amino)-2-oxoethoxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(((1R,3S)-3-(5-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-picolinamido)cyclobutyl)amino)-2-oxoethoxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(((1R,3S)-3-(6-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-nicotinamido)cyclobutyl)amino)-2-oxoethoxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(((1R,3S)-3-(2-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)phenyl)-acetamido)cyclobutyl)amino)-2-oxoethoxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(3-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)piperidine-1-carbonyl)azetidin-1-yl)-2-oxoethoxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(4-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)piperidine-1-carbonyl)piperidin-1-yl)-2-oxoethoxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-(((1R,4S)-4-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)piperidine-1-carbonyl)cyclohexyl)amino)-2-oxoethoxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(2-((2-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)piperidin-1-yl)-2-oxoethyl)amino)-2-oxoethoxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-((1-(1-(4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzoyl)piperidine-4-carbonyl)piperidin-4-yl)methoxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-((1-((4-(2-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)ethyl)benzoyl)glycyl)piperidin-4-yl)methoxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-((1-((4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-3-methoxybenzoyl)glycyl)piperidin-4-yl)methoxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-((1-((4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzoyl)glycyl)piperidin-4-yl)methoxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-((1-((4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-2-methoxybenzoyl)glycyl)piperidin-4-yl)methoxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-((1-(5-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)piperidine-1-carbonyl)thiophene-2-carbonyl)piperidin-4-yl)methoxy)phenyl)-2-phenylacetate;(1-benzylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-((1-((1R,4S)-4-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)piperidine-1-carbonyl)cyclohexane-1-carbonyl)piperidin-4-yl)methoxy)phenyl)-2-phenylacetate;1-benzylpiperidin-4-yl(S)-2-hydroxy-2-(3-(3-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzamido)propoxy)phenyl)-2-phenylacetate;((R)-1-benzylpyrrolidin-3-yl)methyl(S)-2-hydroxy-2-(3-(3-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzamido)-propoxy)phenyl)-2-phenylacetate;((S)-1-benzylpyrrolidin-3-yl)methyl(S)-2-hydroxy-2-(3-(3-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzamido)-propoxy)phenyl)-2-phenylacetate;(1-cyclobutylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(3-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzamido)-propoxy)phenyl)-2-phenylacetate;(1-methylpiperidin-4-yl)methyl(S)-2-hydroxy-2-(3-(3-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzamido)-propoxy)phenyl)-2-phenylacetate;(R)-1-benzylpyrrolidin-3-yl(S)-2-hydroxy-2-(3-(3-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzamido)-propoxy)phenyl)-2-phenylacetate;(S)-1-benzylpyrrolidin-3-yl(S)-2-hydroxy-2-(3-(3-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzamido)-propoxy)phenyl)-2-phenylacetate;1-benzylazetidin-3-yl(S)-2-hydroxy-2-(3-(3-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)benzamido)propoxy)phenyl)-2-phenylacetate;1-benzylpiperidin-4-yl(S)-2-hydroxy-2-(3-((4-((3-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)phenyl)ureido)-methyl)benzyl)oxy)phenyl)-2-phenylacetate;1-benzylpiperidin-4-yl(S)-2-hydroxy-2-(3-((4-((3-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-3-methoxyphenyl)-ureido)methyl)benzyl)oxy)phenyl)-2-phenylacetate;and 1-benzylpiperidin-4-yl(S)-2-hydroxy-2-(3-((4-((3-(4-((((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-2-methoxyphenyl)-ureido)methyl)benzyl)oxy)phenyl)-2-phenylacetate;or a pharmaceutically acceptable salt of said compound.
 28. A methodaccording to claim 18, wherein said broncho-obstructive or inflammatorydisease is asthma, chronic bronchitis, or chronic obstructive pulmonarydisease (COPD).
 29. A method according to claim 18, wherein saidadministering is by inhalation.
 30. A device, which is a single- ormulti-dose dry powder inhaler, a metered dose inhaler, or a soft mistnebulizer and which contains a a compound of formula I

wherein: Q is a group of formula

Y is Y2 or Y1 which are divalent groups of formula

wherein A1 and A2 are independently absent or selected from the groupconsisting of (C₁-C₁₂)alkylene, (C₃-C₈)cycloalkylene, and(C₃-C₈)heterocycloalkylene, each of which are optionally substituted byone or more substituents selected from the group consisting of(C₁-C₆)alkyl, aryl(C₁-C₆)alkyl, and heteroaryl(C₁-C₆)alkyl; B is absentor is selected from the group consisting of (C₃-C₈)cycloalkylene,(C₃-C₈)heterocycloalkylene, arylene, and heteroarylene, each of which isoptionally substituted by one or more groups selected from the groupconsisting of —OH, halogen, —CN, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,(C₁-C₆)haloalkyl, (C₁-C₆)haloalkoxy, and aryl(C₁-C₆)alkyl; C is absentor is selected from the group consisting of —O—, —C(O)—, —OC(O)—,—(O)CO—, —S—, —S(O)—, —S(O)₂—, and —N(R₇)—, or is one of the followinggroups C1-C23

wherein R₇ is in each occurrence independently H or selected from thegroup consisting of linear or branched (C₁-C₈)alkyl, aryl(C₁-C₆)alkyl,arylsulfanyl, arylsulfinyl, arylsulfonyl, (C₃-C₈)cycloalkyl,(C₃-C₈)heterocycloalkyl, aryl, and heteroaryl; D is absent or isselected from the group consisting of (C₁-C₁₂)alkylene,(C₂-C₁₂)alkenylene, (C₂-C₆)alkynylene, arylene, heteroarylene,(C₃-C₈)cycloalkylene, (C₃-C₈)heterocycloalkylene; wherein said arylene,heteroarylene, (C₃-C₈)cycloalkylene, and (C₃-C₈)heterocycloalkylene isoptionally substituted by one or more groups selected from the groupconsisting of —OH, halogen, —CN, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,(C₁-C₆)haloalkyl, (C₁-C₆)haloalkoxy, and aryl(C₁-C₆)alkyl; n is at eachoccurrence independently 0 or an integer from 1 to 3; m is at eachoccurrence independently an integer from 1 to 3; E is absent or isselected from the group consisting of —O—, —NR₇—, —NR₇—C(O)—,—C(O)—NR₇—, —OC(O)—, —C(O)—(CH₂)_(n)—O—; —NR₇—C(O)—(CH₂)_(n)—O—,—NR₇—C(O)—NR₇—, and —S—; G is arylene or heteroarylene, each of which isoptionally substituted by one or more substituents selected from thegroup consisting of halogen, —OH, oxo (═O), —SH, —NO₂, —CN, —CON(R₆)₂,—NH₂, —NHCOR₆, —CO₂R₆, (C₁-C₁₀)alkylsulfanyl, (C₁-C₁₀)alkylsulfinyl,(C₁-C₁₀)alkylsulfonyl, (C₁-C₁₀)alkyl, aryl, haloaryl, heteroaryl, and(C₁-C₁₀)alkoxy; R₁ is selected from the group consisting of(C₃-C₈)cycloalkyl, (C₃-C₈)heterocycloalkyl, aryl, heteroaryl,aryl(C₁-C₆)alkyl, heteroaryl(C₁-C₆)alkyl, and(C₃-C₈)cycloalkyl(C₁-C₆)alkyl, each of which is optionally substitutedby one or more groups selected independently from the group consistingof halogen, (C₁-C₈)alkyl, and (C₁-C₁₀)alkoxy; s is 0 or an integer from1 to 3; R₂ is a nitrogen containing group which is: a group (a) which is—NR₃R₄ wherein R₃ and R₄ are independently hydrogen or (C₁-C₄) alkyl; ora group (b) of formula J1, J2, J3, J4 or J5

R₅ is a group of formula K

wherein p is 0 or an integer from 1 to 4; q is 0 or an integer from 1 to4; P is absent or is a divalent moiety selected from the groupconsisting of O, S, SO, SO₂, CO, NR₆ CH═CH, N(R₆)SO₂, N(R₆)COO,N(R₆)C(O), SO₂N(R₆), OC(O)N(R₆), and C(O)N(R₆); W is H or is selectedfrom the group consisting of (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, aryl, andheteroaryl, each of which is optionally substituted by one or moresubstituents selected independently from the group consisting ofhalogen, —OH, oxo (═O), —SH, —NO₂, —CN, —CON(R₆)₂, —NH₂, —NHCOR₆,—CO₂R₆, (C₁-C₁₀)alkylsulfanyl, (C₁-C₁₀)alkylsulfinyl,(C₁-C₁₀)alkylsulfonyl, (C₁-C₁₀)alkyl, and (C₁-C₁₀)alkoxy; R₆ is at eachoccurrence independently H or selected from the group consisting of(C₁-C₁₀)alkyl, (C₁-C₆)haloalkyl, (C₂-C₆)alkynyl, (C₂-C₆)alkenyl,(C₃-C₈)cycloalkyl, heteroaryl, and aryl, each of which is optionallysubstituted by one or more substituents selected from the groupconsisting of halogen, —OH, oxo (═O), —SH, —NO₂, —CN, —CONH₂, —COOH,(C₁-C₁₀)alkoxycarbonyl, (C₁-C₁₀)alkylsulfanyl, (C₁-C₁₀)alkylsulfinyl, (CC₁₀)alkylsulfonyl, (C₁-C₁₀)alkyl, and (C₁-C₁₀)alkoxy; or apharmaceutically acceptable salt thereof.